U.S. patent application number 14/407282 was filed with the patent office on 2015-06-11 for aromatic heterocyclic compound.
This patent application is currently assigned to MITSUBISHI TANABE PHARMA CORPORATION. The applicant listed for this patent is MITSUBISHI TANABE PHARMA CORPORATION. Invention is credited to Norimitsu Hayashi, Eri Ooboki, Osamu Sakurai, Kunio Saruta, Hiroaki Sawamoto.
Application Number | 20150158844 14/407282 |
Document ID | / |
Family ID | 49758314 |
Filed Date | 2015-06-11 |
United States Patent
Application |
20150158844 |
Kind Code |
A1 |
Saruta; Kunio ; et
al. |
June 11, 2015 |
AROMATIC HETEROCYCLIC COMPOUND
Abstract
The compound represented by the general formula: wherein ring A
is benzene which may be substituted and the like; ring B is benzene
which may be substituted and the like; X is a single bond and the
like; Y is alkyl which may be substituted and the like; Z is
CR.sup.1 or nitrogen atom; R.sup.1 is hydrogen and the like;
R.sup.2 is alkyl which may be substituted and the like or a
pharmaceutically acceptable salt thereof is useful as a
prevention/treatment agent of obesity, diabetes, and the like.
Inventors: |
Saruta; Kunio; (Osaka-shi,
JP) ; Hayashi; Norimitsu; (Osaka-shi, JP) ;
Sakurai; Osamu; (Osaka-shi, JP) ; Sawamoto;
Hiroaki; (Osaka-shi, JP) ; Ooboki; Eri;
(Osaka-shi, JP) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
MITSUBISHI TANABE PHARMA CORPORATION |
Osaka-shi, Osaka |
|
JP |
|
|
Assignee: |
MITSUBISHI TANABE PHARMA
CORPORATION
Osaka-shi, Osaka
JP
|
Family ID: |
49758314 |
Appl. No.: |
14/407282 |
Filed: |
June 14, 2013 |
PCT Filed: |
June 14, 2013 |
PCT NO: |
PCT/JP2013/066431 |
371 Date: |
December 11, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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61660129 |
Jun 15, 2012 |
|
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61660137 |
Jun 15, 2012 |
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Current U.S.
Class: |
514/235.8 ;
514/253.09; 514/255.05; 514/256; 514/318; 514/333; 514/341;
544/131; 544/333; 544/364; 544/405; 546/194; 546/256; 546/269.1;
546/271.4; 546/272.1; 546/272.7; 546/274.1 |
Current CPC
Class: |
C07D 401/10 20130101;
C07D 249/08 20130101; A61P 11/00 20180101; A61P 3/10 20180101; A61P
27/02 20180101; C07D 405/14 20130101; A61P 9/10 20180101; A61P 9/00
20180101; C07D 417/14 20130101; A61P 9/12 20180101; A61P 1/16
20180101; A61P 19/02 20180101; C07D 413/14 20130101; A61P 29/00
20180101; C07D 409/14 20130101; C07D 401/04 20130101; A61P 3/04
20180101; A61P 43/00 20180101; C07D 249/14 20130101; A61P 3/06
20180101; C07D 401/14 20130101 |
International
Class: |
C07D 401/14 20060101
C07D401/14; C07D 405/14 20060101 C07D405/14; C07D 401/10 20060101
C07D401/10; C07D 401/04 20060101 C07D401/04; C07D 413/14 20060101
C07D413/14 |
Claims
1. A compound represented by the general formula (1): ##STR01025##
[wherein ring A is benzene which may be substituted or 6-membered
monocyclic aromatic heterocycle which may be substituted; ring B is
benzene which may be substituted or 6-membered monocyclic aromatic
heterocycle which may be substituted; X is a single bond or --O--;
Y is alkyl which may be substituted or cycloalkyl which may be
substituted; Z is CR.sup.1 or nitrogen atom; R.sup.1 is hydrogen,
halogen atom, alkoxy, or alkyl which may be substituted; (i) when Z
is CR.sup.1, R.sup.2 is the formula as below: ##STR01026## {wherein
Z' represents a single bond, alkylene, -Alk-O--, or
-Alk.sup.1-O-Alk.sup.2-, (wherein Alk, Alk.sup.1, and Alk.sup.2
each independently represent alkylene, and the bond at the right
end represents a bond to ring C), ring C represents an aromatic
hydrocarbon group or an aromatic heterocyclic group}, R.sup.3 and
R.sup.4 each independently represent hydrogen, halogen atom, alkyl
which may be substituted, alkoxy which may be substituted, alkyl
substituted with non-aromatic heterocycle, or carbonyl substituted
with non-aromatic heterocycle; (ii) when Z is nitrogen atom,
R.sup.2 is alkyl which may be substituted, alkoxy which may be
substituted, alkylthio, an aromatic hydrocarbon group which may be
substituted, a non-aromatic heterocyclic group which may be
substituted, cycloalkyl which may be substituted, aryloxy which may
be substituted, heteroaryloxy which may be substituted,
cycloalkyloxy, or cycloalkylalkoxy], or a pharmaceutically
acceptable salt thereof.
2. The compound according to claim 1, wherein the compound is
represented by the general formula (1-A): ##STR01027## [wherein
ring A is benzene which may be substituted or 6-membered monocyclic
aromatic heterocycle which may be substituted; ring B.sup.1 is
benzene which may be substituted or 6-membered monocyclic aromatic
heterocycle which may be substituted; R.sup.1 is hydrogen, halogen
atom, alkoxy, or alkyl which may be substituted; R.sup.2a is the
formula as below: ##STR01028## {wherein Z' represents a single
bond, alkylene, -Alk-O--, or -Alk.sup.1-O-Alk.sup.2-, (wherein Alk,
Alk.sup.1, and Alk.sup.2 each independently represent alkylene, and
the bond at the right end represents a bond to ring C), ring C
represents an aromatic hydrocarbon group or an aromatic
heterocyclic group, R.sup.3 and R.sup.4 each independently
represent hydrogen, halogen atom, alkyl which may be substituted,
alkoxy which may be substituted, alkyl substituted with
non-aromatic heterocycle, or carbonyl substituted with non-aromatic
heterocycle}; X is a single bond or --O--; Y.sup.a is alkyl which
may be substituted or cycloalkyl which may be substituted]; or a
pharmaceutically acceptable salt thereof.
3. The compound according to claim 2 wherein ring A is benzene
which may be substituted or pyridine which may be substituted, or a
pharmaceutically acceptable salt thereof.
4. The compound according to claim 2 wherein ring B.sup.1 is
benzene which may be substituted, pyridine which may be
substituted, or pyrimidine which may be substituted, or a
pharmaceutically acceptable salt thereof.
5. The compound according to claim 2 wherein X is --O--; and
Y.sup.a is alkyl substituted with carboxy, or a pharmaceutically
acceptable salt thereof.
6. The compound according to claim 2 which is selected from
1-{[(5'-fluoro-4-methyl-6'-{5-[2-(trifluoromethoxy)phenyl]-1H-imidazol-2--
yl}-3,3'-bipyridin-6-yl)oxy]methyl}cyclopropanecarboxylic acid,
2,2-dimethyl-3-{[4-methyl-5-(2-{5-[2-(trifluoromethyl)phenyl]-1H-imidazol-
-2-yl}-pyrimidin-5-yl)pyridin-2-yl]oxy}propanoic acid,
3-{[5'-fluoro-4-methyl-6'-(5-phenyl-1H-imidazol-2-yl)-3,3'-bipyridin-6-yl-
]oxy}-2,2-dimethylpropanoic acid,
2-ethyl-2-[({5-[6-(5-phenyl-1H-imidazol-2-yl)pyridin-3-yl]pyrazin-2-yl}ox-
y)methyl]-butanoic acid,
3-[4-(5-{5-[4-(difluoromethoxy)phenyl]-1H-imidazol-2-yl}pyridin-2-yl)phen-
oxy]-2,2-dimethylpropanoic acid,
2,2-dimethyl-3-[4-(5-{5-[2-(trifluoromethoxy)phenyl]-1H-imidazol-2-yl}pyr-
idin-2-yl)-phenoxy]propanoic acid,
2,2-dimethyl-3-(4-{5-[5-(2-phenoxyethyl)-1H-imidazol-2-yl]pyridin-2-yl}ph-
enoxy)-propanoic acid,
2,2-dimethyl-3-({4-methyl-5-[2-(5-phenyl-1H-imidazol-2-yl)pyrimidin-5-yl]-
pyridin-2-yl}oxy)propanoic acid,
2,2-dimethyl-3-({4-methyl-5-[3-methyl-4-(5-phenyl-1H-imidazol-2-yl)phenyl-
]pyridin-2-yl}oxy)propanoic acid,
2,2-dimethyl-3-({5-[3-methyl-4-(5-phenyl-1H-imidazol-2-yl)phenyl]pyridin--
2-yl}oxy)-propanoic acid,
3-(4-{5-[5-(2,4-difluorophenyl)-1H-imidazol-2-yl]pyridin-2-yl}phenoxy)-2,-
2-dimethylpropanoic acid,
2-ethyl-2-[({4-methyl-5-[2-(5-phenyl-1H-imidazol-2-yl)pyrimidin-5-yl]pyri-
din-2-yl}-oxy)methyl]butanoic acid,
1-[({4-methyl-5-[2-(5-phenyl-1H-imidazol-2-yl)pyrimidin-5-yl]pyridin-2-yl-
}oxy)-methyl]cyclobutanecarboxylic acid,
2,2-dimethyl-3-({5-[4-(5-phenyl-1H-imidazol-2-yl)phenyl]pyridin-2-yl}oxy)-
propanoic acid,
3-[(5-{4-[5-(4-methoxyphenyl)-1H-imidazol-2-yl]phenyl}pyridin-2-yl)oxy]-2-
,2-dimethylpropanoic acid,
1-({[5'-fluoro-4-methyl-6'-(5-phenyl-1H-imidazol-2-yl)-3,3'-bipyridin-6-y-
l]oxy}-methyl)cyclopropanecarboxylic acid,
3-[(5-{3-cyano-4-[4-(4-methoxyphenyl)-1H-imidazol-2-yl]phenyl}-4-methylpy-
ridin-2-yl)oxy]-2,2-dimethylpropanoic acid,
2,2-dimethyl-3-[4-(5-{5-[2-(trifluoromethyl)benzyl]-1H-imidazol-2-yl}pyri-
din-2-yl)-phenoxy]propanoic acid,
3-(4-{5-[5-(4-methoxyphenyl)-1H-imidazol-2-yl]pyridin-2-yl}phenoxy)-2,2-d-
imethylpropanoic acid,
2,2-dimethyl-3-({4-methyl-5-[4-(5-phenyl-1H-imidazol-2-yl)phenyl]pyridin--
2-yl}oxy)-propanoic acid,
3-[4-(5-{5-[(benzyloxy)methyl]-1H-imidazol-2-yl}pyridin-2-yl)phenoxy]-2,2-
-dimethylpropanoic acid,
3-{4-[5-(4-chloro-5-phenyl-1H-imidazol-2-yl)pyridin-2-yl]phenoxy}-2,2-dim-
ethyl-propanoic acid,
2,2-dimethyl-3-(4-{5-[5-(thiophen-2-yl)-1H-imidazol-2-yl]pyridin-2-yl}phe-
noxy)-propanoic acid,
3-[(5-{4-[5-(4-methoxyphenyl)-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2--
yl)oxy]-2,2-dimethylpropanoic acid, and
2,2-dimethyl-3-{4-[5-(5-phenyl-1H-imidazol-2-yl)pyridin-2-yl]phenoxy}prop-
anoic acid, or a pharmaceutically acceptable salt thereof.
7. The compound according to claim 1 wherein the compound is
represented by the general formula (1-B): ##STR01029## (wherein
ring A represents benzene which may be substituted or 6-membered
monocyclic aromatic heterocycle which may be substituted; ring
B.sup.2 represents benzene which may be substituted or 6-membered
monocyclic aromatic heterocycle which may be substituted; R.sup.2b
represents alkyl which may be substituted, alkoxy which may be
substituted, alkylthio, an aromatic hydrocarbon group which may be
substituted, a non-aromatic heterocyclic group which may be
substituted, cycloalkyl which may be substituted, aryloxy which may
be substituted, heteroaryloxy which may be substituted,
cycloalkyloxy, or cycloalkylalkoxy, X represents a single bond or
--O--; Y.sup.b represents alkyl which may be substituted or
cycloalkyl which may be substituted); or a pharmaceutically
acceptable salt thereof.
8. The compound according to claim 7 wherein ring A is benzene
which may be substituted or pyridine which may be substituted, or a
pharmaceutically acceptable salt thereof.
9. The compound according claim 7 wherein ring B.sup.2 is benzene
which may be substituted, pyridine which may be substituted or
pyrimidine which may be substituted, or a pharmaceutically
acceptable salt thereof.
10. The compound according to claim 7 wherein R.sup.2b is alkyl
which may be substituted, alkoxy which may be substituted, an
aromatic hydrocarbon group which may be substituted, or aryloxy
which may be substituted, or a pharmaceutically acceptable salt
thereof.
11. The compound according to claim 7 wherein X is --O--, and
Y.sup.b is alkyl which may be substituted with carboxy, or a
pharmaceutically acceptable salt thereof.
12. The compound according to claim 7 which is selected from
2,2-dimethyl-3-[(5-{4-[3-(propan-2-yloxy)-1H-1,2,4-triazol-5-yl]phenyl}py-
ridin-2-yl)-oxy]propanoic acid,
3-[(5-{3-fluoro-4-[3-(propan-2-yloxy)-1H-1,2,4-triazol-5-yl]phenyl}-4-met-
hylpyridin-2-yl)oxy]-2,2-dimethylpropanoic acid,
2,2-dimethyl-3-({4'-methyl-5-[3-(propan-2-yloxy)-1H-1,2,4-triazol-5-yl]-2-
,3'-bipyridin-6'-yl}oxy)propanoic acid,
3-[(5-{4-[3-(4-fluorophenoxy)-1H-1,2,4-triazol-5-yl]phenyl}pyridin-2-yl)o-
xy]-2,2-dimethylpropanoic acid,
3-[(5-{4-[3-(4-cyanophenoxy)-1H-1,2,4-triazol-5-yl]phenyl}pyridin-2-yl)ox-
y]-2,2-dimethylpropanoic acid,
2,2-dimethyl-3-[(5-{4-[3-(2,2,3,3,3-pentafluoropropoxy)-1H-1,2,4-triazol--
5-yl]phenyl}pyridin-2-yl)oxy]propanoic acid sodium salt,
(trans-4-{4'-[3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl]biphenyl-4-yl}cyc-
lohexyl)-acetic acid,
(trans-4-{4-{5-[3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl]pyridin-2-yl}ph-
enyl)-cyclohexyl]acetic acid,
[4-(5-{4-[3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl]phenyl}pyridin-2-yl)c-
yclohexyl]-acetic acid,
2,2-dimethyl-3-({5-[4-(5-phenyl-4H-1,2,4-triazol-3-yl)phenyl]pyridin-2-yl-
}oxy]-propanoic acid,
(4-{5-[4-(3-ethoxy-1H-1,2,4-triazol-5-yl)phenyl]pyridin-2-yl}cyclohexyl)a-
cetic acid,
3-({5-[4-(3-ethoxy-1H-1,2,4-triazol-5-yl)phenyl]-4-methylpyridin-2-yl}oxy-
)-2,2-dimethylpropanoic acid,
2,2-dimethyl-3-({4-methyl-6'-[3-(propan-2-yloxy)-1H-1,2,4-triazol-5-yl]-3-
,3'-bipyridin-6-yl}oxy)propanoic acid,
3-[(5-{4-[3-(2,4-difluorophenoxy)-1H-1,2,4-triazol-5-yl]phenyl}pyridin-2--
yl)oxy]-2,2-dimethylpropanoic acid, and
3-[(5-{3-fluoro-4-[3-(4-fluorophenoxy)-1H-1,2,4-triazol-5-yl]phenyl}-4-me-
thylpyridin-2-yl)oxy]-2,2-dimethylpropanoic acid, or a
pharmaceutically acceptable salt thereof.
13. A diacylglycerol acyltransferase (DGAT) 1 inhibitor comprising
the compound according to claim 1 or a pharmaceutically acceptable
salt thereof as active ingredient.
14. The DGAT 1 inhibitor according to claim 13 which is a
prophylactic or treatment agent of obesity.
15. The DGAT 1 inhibitor according to claim 13 which is a
prophylactic or treatment agent of hyperlipidemia,
hypertriglyceridemia, lipid metabolism disorder or fatty liver.
16. The DGAT 1 inhibitor according to claim 13 wherein the agent is
a prevention/treatment agent of type 2 diabetes mellitus, diabetic
complication (including diabetic peripheral neuropathy, diabetic
nephropathy, diabetic retinopathy and diabetic macroangiopathy),
arteriosclerosis, hypertension, cerebrovascular disorder, coronary
artery disease, dyspnoea, lumbago or gonarthrosis.
17. The DGAT 1 inhibitor according to claim 13 wherein the agent is
a prevention/treatment agent of type 2 diabetes mellitus or
diabetic complication.
18. The DGAT 1 inhibitor according to claim 13 wherein the agent is
a prevention/treatment agent of familial hyperchylomicronemia.
19. Use of the compound according to claim 1 or a pharmaceutically
acceptable salt thereof for the prevention/treatment of
hyperlipidemia, hypertriglyceridemia, lipid metabolism disorder,
fatty liver, type 2 diabetes mellitus, diabetic complication
(including diabetic peripheral neuropathy, diabetic nephropathy,
diabetic retinopathy and diabetic macroangiopathy),
arteriosclerosis, hypertension, cerebrovascular disorder, coronary
artery disease, dyspnoea, lumbago or gonarthrosis.
20. Use of the compound according to claim 1 or a pharmaceutically
acceptable salt thereof for the prevention/treatment of familial
hyperchylomicronemia.
21. A method for the prevention/treatment of hyperlipidemia,
hypertriglyceridemia, lipid metabolism disorder, fatty liver, type
2 diabetes mellitus, diabetic complication (including diabetic
peripheral neuropathy, diabetic nephropathy, diabetic retinopathy
and diabetic macroangiopathy), arteriosclerosis, hypertension,
cerebrovascular disorder, coronary artery disease, dyspnoea,
lumbago or gonarthrosis, characterized by administering the
compound according to claim 1 or a pharmaceutically acceptable salt
thereof to a patient.
22. A method for the prevention/treatment of familial
hyperchylomicronemia, characterized by administering the compound
according to claim 1 or a pharmaceutically acceptable salt thereof
to a patient.
Description
TECHNICAL FIELD
[0001] The present invention relates to an aromatic heterocyclic
compound or a pharmaceutically acceptable salt thereof having an
acylcoenzyme A: diacylglycerolacyltransferase (DGAT) 1 inhibitory
activity.
BACKGROUND ART
[0002] Obesity is a condition wherein fat is excessively
accumulated in a body (Non-Patent Document 1), and may lead to
hyperlipidemia, hypertriglycemia, lipid metabolism disorder, fatty
liver, diabetes, hypertension, arteriosclerosis, cerebrovascular
disorder, coronary artery disease, dyspnoea, lumbago, gonarthrosis,
and the like. Among obesity, those having these diseases or those
which may possibly cause these diseases in the future are defined
as adiposity, and regarded as one of diseases.
[0003] DGAT is an enzyme catalyzing a reaction from diacylglyerol
to TG, which reaction is the final stage of triacylglycerol (TG)
synthesis, and it is known that DGAT has two kinds of subtypes,
DGAT1 and DGAT2. Among these, DGAT1 is known to exist in liver,
skeletal muscle, adipocytes, and the like, and is involved in the
TG synthesis in each tissue (Non-Patent Document 2).
[0004] Further, when TG is absorbed in the small intestine, TG is
decomposed by pancreatic lipase in the lumen of the small intestine
to fatty acid and mono acylglycerol, then incorporated into small
intestinal epithelial cells, and absorbed after it is resynthesized
to TG in the epithelial cells, and it has been known that DGAT1 is
also involved in the final stage of TG resynthesis in the small
intestinal epithelial cells (Non-Patent Document 3).
[0005] Therefore, a compound which inhibits DGAT1 is expected to
improve the pathology of obesity since it not only inhibits TG
synthesis in adipocyte, liver and the like by inhibiting the final
step of TG synthesis but also suppresses the TG absorption in small
intestines by suppressing the TG resynthesis in small intestine
(Non-Patent Document 4).
[0006] Further, a theory that the accumulation of TG in liver,
skeletal muscle, and the like (ectopic fat accumulation) is a cause
of insulin resistance in type 2 diabetes mellitus accompanying
obesity has been widely accepted, and a compound which inhibits
DGAT1 is expected to improve the insulin sensitivity and has the
therapeutic effect on type 2 diabetes mellitus by alleviating the
ectopic fat accumulation (Non-Patent Document 4). Furthermore, in a
mouse deleted in DGAT1 by genetic manipulation (DGAT1 knockout
mouse), it was reported that the improvement in the insulin
sensitivity was observed as compared with a wild type mouse
(Non-Patent Document 5). It was recently reported that a compound
which inhibits DGAT1 stimulates the action of glucagon-like
peptide-1 (GLP-1) and a protein which causes anorexia (Non-Patent
Document 6).
[0007] As a compound having a continuous aromatic ring structure,
the following has been known. For example, in Patent Document 1,
(2S)-2-[4'-(1-benzyl-1H-benzimidazole-2-yl)-biphenyl-4-yloxy]-3-phenyl-pr-
opionic acid (Example 70) and the like are disclosed as a compound
which inhibits protein-tyrosine phosphatase (PTPases) and is useful
for the treatment of insulin resistance accompanying obesity,
glucose intolerance, diabetes, hypertension, or ischemic
disease.
[0008] In Patent Document 2, as a compound having an inhibitory
activity against protein-tyrosine phosphatase 1B (PTP-1B) which is
useful for the treatment of type 2 diabetes mellitus,
2-benzyl-4-[4'-(2-benzyl-benzofuran-3-yl)-biphenyl-4-yl]-4-oxo-butyric
acid (Example 1),
({4'-(3-benzylamino)imidazo[1,2-a]pyridin-2-yl)biphenyl-4-yl}oxy)(phenyl)-
acetic acid,
{[4'-(5-methyl-1H-indol-1-yl)biphenyl-4-yl]oxy}(phenyl) acetic acid
(Example 3), and the like are disclosed.
[0009] In Patent Document 3, Patent Document 4 and Patent Document
5, a compound having an inhibitory activity against Factor VIIa,
Factor IXa, Factor Xa, and/or Factor XIa which has a structure
wherein biphenyl and nitrogen-containing fused heterocyclic ring
are bonded is disclosed. However, the chemical structure is
restricted to those having a structure wherein the
nitrogen-containing fused heterocyclic ring is bonded at the
3-position of the biphenyl.
[0010] In Patent Document 6,
2-[[2'-(5-phenyl-1H-imidazol-2-yl)[1,1'-biphenyl]-3-yl]oxy]acetic
acid (Example 46) and the like as a compound having the therapeutic
effect on obesity and diabetes by inhibiting adipocyte fatty
acid-binding protein (aP2) are disclosed.
[0011] In Non-Patent Document 7,
2-[[2'-(1-ethyl-4,5-diphenyl-1H-imidazol-2-yl)
[1,1'-biphenyl]-3-yl]oxy]acetic acid,
2-[[2'-(4,5-diphenyl-1H-imidazol-2-yl)[1,1'-biphenyl]-3-yl]oxy]acetic
acid, and the like as a compound which binds to adipocyte fatty
acid-binding protein (aFABP) are reported.
[0012] As another compound having a continuous ring structure,
those in, for example, Patent Documents 7 to 14 and Non-Patent
Document 8 are known.
[0013] Also, as a compound having DGAT1 inhibitory activity, for
example, heteroarylbenzene derivatives (Patent Document 15),
bicyclic heterocyclic compounds (Patent Document 16),
triazolopyridine derivatives (Patent Document 17), imidazole
derivatives (Patent Documents 18 to 20), spiro-ring compounds
(Patent Document 21), and biaryl compounds (Patent Document 22) are
known.
PRIOR ART DOCUMENTS
Patent Documents
[0014] Patent Document 1: WO99/58518A [0015] Patent Document 2:
WO2004/99168A [0016] Patent Document 3: WO2003/6670A [0017] Patent
Document 4: WO2003/6011A [0018] Patent Document 5: US2003/0114457A
[0019] Patent Document 6: WO00/59506A [0020] Patent Document 7:
WO2006/034440 [0021] Patent Document 8: WO2011/002067 [0022] Patent
Document 9: JP1994/116251 [0023] Patent Document 10: WO2003/093248
[0024] Patent Document 11: WO2000/066578 [0025] Patent Document 12:
WO2009/079593 [0026] Patent Document 13: WO1995/015594 [0027]
Patent Document 14: WO2003/064410 [0028] Patent Document 15:
WO2009/011285 [0029] Patent Document 16: WO2010/107765 [0030]
Patent Document 17: WO2009/126861 [0031] Patent Document 18:
WO2012/015693 [0032] Patent Document 19: WO2012/047772 [0033]
Patent Document 20: WO2012/044567 [0034] Patent Document 21:
WO2012/009217 [0035] Patent Document 22: WO2008/067257
Non-Patent Documents
[0035] [0036] Non-Patent Document 1: Nanzando's Medical Dictionary
(19.sup.th Edition), page 2113, 2006 [0037] Non-Patent Document 2:
Proc. Natl. Acad. Sci. USA, Vol. 95, page 13018, 1998 [0038]
Non-Patent Document 3: J. Biol. Chem. Vol. 278, page 18532, 2003
[0039] Non-Patent Document 4: Arterioscler. Thromb. Vasc. Biol.
Vol. 25, page 482, 2005 [0040] Non-Patent Document 5: The Journal
of Clinical Investigation, 109(8) 1049-1055 (2002) [0041]
Non-Patent Document 6: American Chemical Society National Meeting
Abst. MEDI 315 (2010) [0042] Non-Patent Document 7: Bioorganic
& Medicinal Chemistry Letters 17(12) 3511-3515, 2007 [0043]
Non-Patent Document 8: J. Med. Chem. 50(13), 3086-3100 (2007)
DISCLOSURE OF THE INVENTION
Problems to be Solved by the Invention
[0044] An object of the present invention is to provide an aromatic
heterocyclic compound or a pharmaceutically acceptable salt thereof
having DGAT1 inhibitory activity, and a DGAT1 inhibitor which is
useful for the prevention and/or treatment of obesity, or
hyperlipidemia, hypertriglyceridemia, lipid metabolism disorder,
fatty liver, hypertension, arteriosclerosis, diabetes, and the like
caused by obesity.
Means to Solve the Problems
[0045] As a result that the inventors of present invention have
conducted earnest studies to solve the aforementioned problems, and
as a result they have found the aromatic heterocyclic compound or a
pharmaceutically acceptable salt thereof represented by a formula
as below has an excellent DGAT1 inhibitory activity and
accomplished the present invention.
[0046] Namely, the present invention is as follows:
1. A compound represented by the general formula (1):
##STR00001##
[wherein
[0047] ring A is benzene which may be substituted or 6-membered
monocyclic aromatic heterocycle which may be substituted;
[0048] ring B is benzene which may be substituted or 6-membered
monocyclic aromatic heterocycle which may be substituted;
[0049] X is a single bond or --O--;
[0050] Y is alkyl which may be substituted or cycloalkyl which may
be substituted;
[0051] Z is CR.sup.1 or nitrogen atom;
[0052] R.sup.1 is hydrogen, halogen atom, alkoxy, or alkyl which
may be substituted;
[0053] (i) when Z is CR.sup.1, R.sup.2 is the formula as below:
##STR00002##
{wherein Z' represents a single bond, alkylene, -Alk-O--, or
-Alk.sup.1-O-Alk.sup.2-, (wherein Alk, Alk.sup.1, and Alk.sup.2
each independently represent alkylene, and the bond at the right
end represents a bond to ring C),
[0054] ring C represents an aromatic hydrocarbon group or an
aromatic heterocyclic group},
[0055] R.sup.3 and R.sup.4 each independently represent hydrogen,
halogen atom, alkyl which may be substituted, alkoxy which may be
substituted, alkyl substituted with non-aromatic heterocycle, or
carbonyl substituted with non-aromatic heterocycle); (ii) when Z is
nitrogen atom, R.sup.2 is alkyl which may be substituted, alkoxy
which may be substituted, alkylthio, an aromatic hydrocarbon group
which may be substituted, a non-aromatic heterocyclic group which
may be substituted, cycloalkyl which may be substituted, aryloxy
which may be substituted, heteroaryloxy which may be substituted,
cycloalkyloxy, or cycloalkylalkoxy],
[0056] or a pharmaceutically acceptable salt thereof.
2. The compound according to the above 1, wherein the compound is
represented by the general formula (1-A):
##STR00003##
[wherein
[0057] ring A is benzene which may be substituted or 6-membered
monocyclic aromatic heterocycle which may be substituted;
[0058] ring B.sup.1 is benzene which may be substituted or
6-membered monocyclic aromatic heterocycle which may be
substituted;
[0059] R.sup.1 is hydrogen, halogen atom, alkoxy, or alkyl which
may be substituted;
[0060] R.sup.2a is the formula as below:
##STR00004##
{wherein Z' represents a single bond, alkylene, -Alk-O--, or
-Alk.sup.1-O-Alk.sup.2-, (wherein Alk, Alk.sup.1, and Alk.sup.2
each independently represent alkylene, and the bond at the right
end represents a bond to ring C),
[0061] ring C represents an aromatic hydrocarbon group or an
aromatic heterocyclic group,
[0062] R.sup.3 and R.sup.4 each independently represent hydrogen,
halogen atom, alkyl which may be substituted, alkoxy which may be
substituted, alkyl substituted with non-aromatic heterocycle, or
carbonyl substituted with non-aromatic heterocycle};
[0063] X is a single bond or --O--;
[0064] Y.sup.a is alkyl which may be substituted or cycloalkyl
which may be substituted];
[0065] or a pharmaceutically acceptable salt thereof.
3. The compound according to the above 2 wherein ring A is benzene
which may be substituted or pyridine which may be substituted, or a
pharmaceutically acceptable salt thereof. 4. The compound according
to the above 2 or 3 wherein ring B.sup.1 is benzene which may be
substituted, pyridine which may be substituted, or pyrimidine which
may be substituted, or a pharmaceutically acceptable salt thereof.
5. The compound according to any one of the above 2 to 4 wherein X
is --O--; and Y.sup.a is alkyl substituted with carboxy, or a
pharmaceutically acceptable salt thereof 6. The compound according
to the above 2 which is selected from [0066]
1-{[(5'-fluoro-4-methyl-6'-{5-[2-(trifluoromethoxy)phenyl]-1H-imidazol-2--
yl}-3,3'-bipyridin-6-yl)oxy]methyl}cyclopropanecarboxylic acid,
[0067]
2,2-dimethyl-3-{[4-methyl-5-(2-{5-[2-(trifluoromethyl)phenyl]-1H-imidazol-
-2-yl}-pyrimidin-5-yl)pyridin-2-yl]oxy}propanoic acid, [0068]
3-{[5'-fluoro-4-methyl-6'-(5-phenyl-1H-imidazol-2-yl)-3,3'-bipyridin-6-yl-
]oxy}-2,2-dimethylpropanoic acid, [0069]
2-ethyl-2-[({5-[6-(5-phenyl-1H-imidazol-2-yl)pyridin-3-yl]pyrazin-2-yl}ox-
y)methyl]-butanoic acid, [0070]
3-[4-(5-{5-[4-(difluoromethoxy)phenyl]-1H-imidazol-2-yl}pyridin-2-yl)phen-
oxy]-2,2-dimethylpropanoic acid, [0071]
2,2-dimethyl-3-[4-(5-{5-[2-(trifluoromethoxy)phenyl]-1H-imidazol-2-yl}pyr-
idin-2-yl)-phenoxy]propanoic acid, [0072]
2,2-dimethyl-3-(4-{5-[5-(2-phenoxyethyl)-1H-imidazol-2-yl]pyridin-2-yl}ph-
enoxy)-propanoic acid, [0073]
2,2-dimethyl-3-({4-methyl-5-[2-(5-phenyl-1H-imidazol-2-yl)pyrimidin-5-yl]-
pyridin-2-yl}oxy)propanoic acid, [0074]
2,2-dimethyl-3-({4-methyl-5-[3-methyl-4-(5-phenyl-1H-imidazol-2-yl)phenyl-
]pyridin-2-yl}oxy)propanoic acid, [0075]
2,2-dimethyl-3-({5-[3-methyl-4-(5-phenyl-1H-imidazol-2-yl)phenyl]pyridin--
2-yl}oxy)-propanoic acid, [0076]
3-(4-{5-[5-(2,4-difluorophenyl)-1H-imidazol-2-yl]pyridin-2-yl}phenoxy)-2,-
2-dimethylpropanoic acid, [0077]
2-ethyl-2-[({4-methyl-5-[2-(5-phenyl-1H-imidazol-2-yl)pyrimidin-5-yl]pyri-
din-2-yl}-oxy)methyl]butanoic acid, [0078]
1-[({4-methyl-5-[2-(5-phenyl-1H-imidazol-2-yl)pyrimidin-5-yl]pyridin-2-yl-
}oxy)-methyl]cyclobutanecarboxylic acid, [0079]
2,2-dimethyl-3-({5-[4-(5-phenyl-1H-imidazol-2-yl)phenyl]pyridin-2-yl}oxy)-
propanoic acid, [0080]
3-[(5-{4-[5-(4-methoxyphenyl)-1H-imidazol-2-yl]phenyl}pyridin-2-yl)oxy]-2-
,2-dimethylpropanoic acid, [0081]
1-({[5'-fluoro-4-methyl-6'-(5-phenyl-1H-imidazol-2-yl)-3,3'-bipyridin-6-y-
l]oxy}-methyl)cyclopropanecarboxylic acid, [0082]
3-[(5-{3-cyano-4-[4-(4-methoxyphenyl)-1H-imidazol-2-yl]phenyl}-4-methylpy-
ridin-2-yl)oxy]-2,2-dimethylpropanoic acid, [0083]
2,2-dimethyl-3-[4-(5-{5-[2-(trifluoromethyl)benzyl]-1H-imidazol-2-yl}pyri-
din-2-yl)-phenoxy]propanoic acid, [0084]
3-(4-{5-[5-(4-methoxyphenyl)-1H-imidazol-2-yl]pyridin-2-yl}phenoxy)-2,2-d-
imethylpropanoic acid, [0085]
2,2-dimethyl-3-({4-methyl-5-[4-(5-phenyl-1H-imidazol-2-yl)phenyl]pyridin--
2-yl}oxy)-propanoic acid, [0086]
3-[4-(5-{5-[(benzyloxy)methyl]-1H-imidazol-2-yl}pyridin-2-yl)phenoxy]-2,2-
-dimethylpropanoic acid, [0087]
3-{4-[5-(4-chloro-5-phenyl-1H-imidazol-2-yl)pyridin-2-yl]phenoxy}-2,2-dim-
ethylpropanoic acid, [0088]
2,2-dimethyl-3-(4-{5-[5-(thiophen-2-yl)-1H-imidazol-2-yl]pyridin-2-yl}phe-
noxy)-propanoic acid, [0089]
3-[(5-{4-[5-(4-methoxyphenyl)-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2--
yl)oxy]-2,2-dimethylpropanoic acid, and [0090]
2,2-dimethyl-3-{4-[5-(5-phenyl-1H-imidazol-2-yl)pyridin-2-yl]phenoxy}prop-
anoic acid, or a pharmaceutically acceptable salt thereof 7. The
compound according to the above 1 wherein the compound is
represented by the general formula (1-B):
##STR00005##
[0090] (wherein ring A represents benzene which may be substituted
or 6-membered monocyclic aromatic heterocycle which may be
substituted;
[0091] ring B.sup.2 represents benzene which may be substituted or
6-membered monocyclic aromatic heterocycle which may be
substituted;
[0092] R.sup.2b represents alkyl which may be substituted, alkoxy
which may be substituted, alkylthio, an aromatic hydrocarbon group
which may be substituted, a non-aromatic heterocyclic group which
may be substituted, cycloalkyl which may be substituted, aryloxy
which may be substituted, heteroaryloxy which may be substituted,
cycloalkyloxy, or cycloalkylalkoxy,
[0093] X represents a single bond or --O--;
[0094] Y.sup.b represents alkyl which may be substituted or
cycloalkyl which may be substituted);
[0095] or a pharmaceutically acceptable salt thereof.
8. The compound according to the above 7 wherein ring A is benzene
which may be substituted or pyridine which may be substituted, or a
pharmaceutically acceptable salt thereof. 9. The compound according
to the above 7 or 8 wherein ring B.sup.2 is benzene which may be
substituted, pyridine which may be substituted or pyrimidine which
may be substituted, or a pharmaceutically acceptable salt thereof.
10. The compound according to any one of the above 7 to 9 wherein
R.sup.2b is alkyl which may be substituted, alkoxy which may be
substituted, an aromatic hydrocarbon group which may be
substituted, or aryloxy which may be substituted, or a
pharmaceutically acceptable salt thereof. 11. The compound
according to any one of the above 7 to 10 wherein X is --O--, and
Y.sup.b is alkyl which may be substituted with carboxy, or a
pharmaceutically acceptable salt thereof. 12. The compound
according to the above 7 which is selected from [0096]
2,2-dimethyl-3-[(5-{4-[3-(propan-2-yloxy)-1H-1,2,4-triazol-5-yl]phenyl}-p-
yridin-2-yl)oxy]propanoic acid, [0097]
3-[(5-{3-fluoro-4-[3-(propan-2-yloxy)-1H-1,2,4-triazol-5-yl]phenyl}-4-met-
hylpyridin-2-yl)oxy]-2,2-dimethylpropanoic acid, [0098]
2,2-dimethyl-3-({4'-methyl-5-[3-(propan-2-yloxy)-1H-1,2,4-triazol-5-yl]-2-
,3'-bipyridin-6'-yl}oxy)propanoic acid, [0099]
3-[(5-{4-[3-(4-fluorophenoxy)-1H-1,2,4-triazol-5-yl]phenyl}pyridin-2-yl)o-
xy]-2,2-dimethylpropanoic acid, [0100]
3-[(5-{4-[3-(4-cyanophenoxy)-1H-1,2,4-triazol-5-yl]phenyl}pyridin-2-yl)ox-
y]-2,2-dimethylpropanoic acid, [0101]
2,2-dimethyl-3-[(5-{4-[3-(2,2,3,3,3-pentafluoropropoxy)-1H-1,2,4-triazol--
5-yl]phenyl}pyridin-2-yl)oxy]propanoic acid sodium salt, [0102]
(trans-4-{4'-[3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl]biphenyl-4-yl}cyc-
lohexyl)acetic acid, [0103]
(trans-4-{4-{5-[3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl]pyridin-2-yl}ph-
enyl)-cyclohexyl]acetic acid, [0104]
[4-(5-{4-[3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl]phenyl}pyridin-2-yl)c-
yclohexyl]-acetic acid, [0105]
2,2-dimethyl-3-({5-[4-(5-phenyl-4H-1,2,4-triazol-3-yl)phenyl]pyridin-2-yl-
}oxy]-propanoic acid, [0106]
(4-{5-[4-(3-ethoxy-1H-1,2,4-triazol-5-yl)phenyl]pyridin-2-yl}cyclohexyl)a-
cetic acid, [0107]
3-({5-[4-(3-ethoxy-1H-1,2,4-triazol-5-yl)phenyl]-4-methylpyridin-2-yl}oxy-
)-2,2-dimethylpropanoic acid, [0108]
2,2-dimethyl-3-({4-methyl-6'-[3-(propan-2-yloxy)-1H-1,2,4-triazol-5-yl]-3-
,3'-bipyridin-6-yl}oxy)propanoic acid, [0109]
3-[(5-{4-[3-(2,4-difluorophenoxy)-1H-1,2,4-triazol-5-yl]phenyl}pyridin-2--
yl)oxy]-2,2-dimethylpropanoic acid, and [0110]
3-[(5-{3-fluoro-4-[3-(4-fluorophenoxy)-1H-1,2,4-triazol-5-yl]phenyl}-4-me-
thylpyridin-2-yl)oxy]-2,2-dimethylpropanoic acid, or a
pharmaceutically acceptable salt thereof 13. A diacylglycerol
acyltransferase (DGAT) 1 inhibitor comprising the compound
according to any one of the above 1 to 12 or a pharmaceutically
acceptable salt thereof as active ingredient. 14. The DGAT 1
inhibitor according to the above 13 which is a prophylactic or
treatment agent of obesity. 15. The DGAT 1 inhibitor according to
the above 13 which is a prophylactic or treatment agent of
hyperlipidemia, hypertriglyceridemia, lipid metabolism disorder or
fatty liver. 16. The DGAT 1 inhibitor according to the above 13
wherein the agent is a prevention/treatment agent of type 2
diabetes mellitus, diabetic complication (including diabetic
peripheral neuropathy, diabetic nephropathy, diabetic retinopathy
and diabetic macroangiopathy), arteriosclerosis, hypertension,
cerebrovascular disorder, coronary artery disease, dyspnoea,
lumbago or gonarthrosis. 17. The DGAT 1 inhibitor according to the
above 13 wherein the agent is a prevention/treatment agent of type
2 diabetes mellitus or diabetic complication. 18. The DGAT 1
inhibitor according to the above 13 wherein the agent is a
prevention/treatment agent of familial hyperchylomicronemia. 19.
Use of the compound according to any one of the above 1 to 12 or a
pharmaceutically acceptable salt thereof for the
prevention/treatment of hyperlipidemia, hypertriglyceridemia, lipid
metabolism disorder, fatty liver, type 2 diabetes mellitus,
diabetic complication (including diabetic peripheral neuropathy,
diabetic nephropathy, diabetic retinopathy and diabetic
macroangiopathy), arteriosclerosis, hypertension, cerebrovascular
disorder, coronary artery disease, dyspnoea, lumbago or
gonarthrosis. 20. Use of the compound according to any one of the
above 1 to 12 or a pharmaceutically acceptable salt thereof for the
prevention/treatment of familial hyperchylomicronemia. 21. A method
for the prevention/treatment of hyperlipidemia,
hypertriglyceridemia, lipid metabolism disorder, fatty liver, type
2 diabetes mellitus, diabetic complication (including diabetic
peripheral neuropathy, diabetic nephropathy, diabetic retinopathy
and diabetic macroangiopathy), arteriosclerosis, hypertension,
cerebrovascular disorder, coronary artery disease, dyspnoea,
lumbago or gonarthrosis, characterized by administering the
compound according to any one of the above 1 to 12 or a
pharmaceutically acceptable salt thereof to a patient. 22. A method
for the prevention/treatment of familial hyperchylomicronemia,
characterized by administering the compound according to any one of
the above 1 to 12 or a pharmaceutically acceptable salt thereof to
a patient.
[0111] Another aspect of the present invention includes a compound
represented by the general formula (A) as below:
##STR00006##
[wherein
[0112] ring A represents benzene which may be substituted or
6-membered monocyclic aromatic heterocycle which may be
substituted;
[0113] ring B.sup.1 represents benzene which may be substituted or
6-membered monocyclic aromatic heterocycle which may be
substituted;
[0114] X.sup.A represents a single bond or --O--;
[0115] Y.sup.A represents:
(1) cycloalkyl which may be substituted with the group selected
from (i) to (v) as below:
[0116] (i) carboxy,
[0117] (ii) carboxyalkyl
[0118] (iii) alkoxyalkyl
[0119] (iv) aminocarbonyl, and
[0120] (v) alkoxycarbonylalkyl, or
(2) alkyl which may be substituted with a group selected from (i)
and (ii) as below:
[0121] (i) carboxy, and
[0122] (ii) aminocarbonyl which may be mono- or di-substituted with
alkyl which may be substituted with 1 to 3 hydroxyls,
[0123] R.sub.1A represents hydrogen, alkyl, or halogen atom;
and
[0124] R.sup.2A represents (1) alkyl which may be substituted with
a group selected from halogen atom, alkoxy, and hydroxy, (2)
halogen atom, (3) cyano, (4) aminocarbonyl which may be mono- or
di-substituted with alkyl, (5) alkoxycarbonyl, or (6)
tetrahydropyranyl;
[0125] with the proviso that when R.sup.1A is hydrogen atom;
R.sup.2A is alkyl which may be substituted with halogen atom; ring
A is:
##STR00007##
(wherein a bond at the right end represents a bond to ring B,
X.sub.1 represents N or CRX.sub.1, X.sub.2 represents N or
CRX.sub.2, X.sub.3 represents N or CRX.sub.3, X.sub.4 represents N
or CRX.sub.4, RX.sub.1, RX.sub.2, RX.sub.3 and RX.sub.4 each
represents hydrogen, straight or branched alkyl which may be
substituted with halogen atom, alkyl having a cyclic structure
which may be substituted with halogen atom, straight or branched
alkoxy, halogen atom, or cyano),
[0126] then an aspect wherein Y.sup.A is alkyl substituted with
carboxy, and X.sup.A is --O-- is excluded,
[0127] or a pharmaceutically acceptable salt thereof.]
[0128] Another aspect of the present invention includes a compound
represented by the general formula (B) as below:
##STR00008##
(wherein ring B.sup.3 represents 6-membered monocyclic aromatic
heterocycle which may be substituted;
[0129] P represents hydrogen or alkyl,
[0130] Q represents hydrogen, or a group which forms carbonyl
together with P,
[0131] X.sup.B represents a single bond or --CH.sub.2CO-- wherein a
bond at the right end represents a bond to piperazine,
Y.sup.B represents: (1) phenyl which may be substituted with a
group selected from (i) to (vi) as below:
[0132] (i) halogen atom,
[0133] (ii) alkyl,
[0134] (iii) carboxyalkyl
[0135] (iv) hydroxyalkyl
[0136] (v) alkoxycarbonylalkyl which may be substituted with a
group selected from hydroxy, aralkyloxy, and
2,2-dimethyl-1,3-dioxolane, and
[0137] (vi) aminocarbonylalkyl which may be mono- or di-substituted
with alkyl which may be substituted with a group selected from
hydroxy and 2,2-dimethyl-1,3-dioxolane,
(2) pyridyl which may be substituted with alkyl, or (3) alkyl which
may be substituted with carboxy,
[0138] R.sup.1B represents hydrogen or alkyl, and
[0139] R.sup.2B represents cycloalkyl or alkyl which may be
substituted with halogen),
[0140] or a pharmaceutically acceptable salt thereof.
[0141] Another aspect of the present invention also includes a
compound represented by the general formula (C) as below:
##STR00009##
[wherein ring B.sup.1 represents benzene which may be substituted
or 6-membered monocyclic aromatic heterocycle which may be
substituted,
[0142] X.sup.C represents a single bond, --O--, --OCH.sub.2--
(wherein a bond at the right end represents a bond to piperizine,
or alkylene),
[0143] Y.sup.C represents:
(1) phenyl which may be substituted with a group selected from (i)
to (v) as below:
[0144] (i) halogen atom,
[0145] (ii) alkyl,
[0146] (iii) carboxyalkyl
[0147] (iv) carboxy, and
[0148] (v) alkoxy, or
(2) alkyl which may be substituted with carboxy, and
[0149] R.sup.2C represents alkyl which may be substituted with
halogen],
or a pharmaceutically acceptable salt thereof.[0043]
[0150] Further, another aspect of the present invention includes a
compound represented by the general formula (D) as below:
##STR00010##
[wherein ring B.sup.3 represents 6-membered monocyclic aromatic
heterocyclic ring which may be substituted,
[0151] X.sup.D represents a single bond, --OCH.sub.2-- or --O--
(wherein a bond at the right end represents a bond to
cyclohexane),
[0152] Y.sup.D represents:
(1) phenyl which may be substituted with a group selected from (i)
to (iv) as below:
[0153] (i) halogen atom,
[0154] (ii) alkyl,
[0155] (iii) carboxyalkyl, and
[0156] (iv) carboxy
(2) pyridyl which may be substituted with carboxy, or (3) alkyl
which may be substituted with carboxy, and
[0157] R.sup.2D represents alkyl which may be substituted with
halogen],
[0158] or a pharmaceutically acceptable salt thereof.
[0159] The groups represented by each symbol in the present
specification are explained below. The abbreviations used in the
present specification each have the meanings as below. [0160] Ac:
acetyl [0161] Bn: benzyl [0162] Boc: t-butoxycarbonyl [0163] EDC:
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide [0164] Et: ethyl
[0165] HOBt: 1-hydroxybenzotriazole [0166] Me: methyl [0167] MOM:
methoxymethyl [0168] Ph: phenyl [0169] SEM:
2-(trimethylsilyl)ethoxymethyl [0170] TBS: t-butyldimethylsilyl
[0171] t-Bu: t-butyl [0172] Tf: trifluoromethanesulfonyl [0173]
TFA: trifluoroacetic acid [0174] THF: tetrahydrofuran [0175] TMS:
trimethylsilyl
[0176] As "halogen atom", fluorine atom, chlorine atom, bromine
atom, and iodine atom can be mentioned. Among them, fluorine atom
and chlorine atom are preferred.
[0177] As "alkyl", for example, straight or branched alkyl having 1
to 8 carbon atom, preferably 1 to 6 carbon atoms, can be mentioned,
and specifically, methyl, ethyl, propyl, isopropyl, butyl, t-butyl,
isobutyl, pentyl, hexyl, 2-methylpropyl, 2-ethylbutyl,
2-propylpentyl, and the like can be mentioned.
[0178] As "cycloalkane", for example, cycloalkane having 3 to 8
carbon atoms, preferably 3 to 6 carbon atoms, can be mentioned, and
specifically, cyclopropane, cyclobutane, cyclopentane, cyclohexane,
cycloheptane, and the like can be mentioned.
[0179] As "cycloalkyl", for example, cycloalkyl having 3 to 8
carbon atoms, preferably 3 to 6 carbon atom, can be mentioned, and
specifically, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, and the like can be mentioned.
[0180] As "alkoxy", for example, straight or branched alkoxy having
1 to 8 carbon atom, preferably 1 to 6 carbon atoms, can be
mentioned, and specifically, methoxy, ethoxy, propoxy, isopropoxy,
butoxy, t-butoxy, isobutoxy, pentyloxy, hexyloxy, and the like can
be mentioned.
[0181] As "alkylene", for example, straight or branched alkylene
having 1 to 6 carbon atom, preferably 1 to 3 carbon atoms, can be
mentioned, and specifically, methylene, ethylene, propylene,
isopropylene, butylene, isobutylene, and the like can be
mentioned.
[0182] As "alkoxycarbony", for example, straight or branched
alkoxycarbonyl having 2 to 9 carbon atoms, can be mentioned, and
specifically, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
isopropoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl,
hexyloxycarbonyl, and the like can be mentioned.
[0183] As "alkoxycarbonylalkyl", for example, the above "alkyl"
substituted with the above "alkoxycarbonyl" can be mentioned, and
specifically, methoxycarbonylmethyl, methoxycarbonylethyl,
ethoxycarbonylmethyl, ethoxycarbonylethyl, and the like can be
mentioned.
[0184] As "carboxyalkyl", for example, the above "alkyl"
substituted with carboxy can be mentioned, and specifically,
carboxymethyl, carboxyethyl, carboxypropyl, carboxyisopropyl,
carboxy-t-butyl, carboxyhexyl, and the like can be mentioned.
[0185] As "alkoxyalkyl", for example, the above "alkyl" substituted
with the above "alkoxy" can be mentioned, and specifically,
methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl,
t-butoxymethyl, and the like can be mentioned.
[0186] As "hydroxyalkyl", for example, the above "alkyl"
substituted with hydroxy can be mentioned, and specifically,
hydroxymethyl, 1-hydroxyethyl, 2-hydroxypropyl, 2-hydroxyethyl,
3-hydroxypropyl, and the like can be mentioned.
[0187] As "aminocarbonylalkyl", for example, the above "alkyl"
substituted with aminocarbonyl can be mentioned, and specifically,
aminocarbonylmethyl, aminocarbonylethyl, and the like can be
mentioned.
[0188] As "aromatic hydrocarbon group", for example, 6 to 14
membered monocyclic, bicyclic, or tricyclic aromatic hydrocarbon
group can be mentioned, specifically, phenyl, naphthyl,
phenanthryl, anthryl, and the like can be mentioned, and phenyl is
particularly preferred.
[0189] As "aromatic heterocyclic group", for example, 5 to 14
membered mono-cyclic or bi-cyclic aromatic heterocyclic group
containing 1 to 4 heteroatoms selected from nitrogen atom, sulfur
atom and oxygen atom other than carbon atom as an annular atom can
be mentioned, and specifically, pyrrolyl, imidazolyl, triazolyl,
tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,
triazinyl, azepinyl, diazepinyl, furyl, pyranyl, oxepinyl, thienyl,
thiopyranyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,
furazanyl, oxadiazolyl, oxazinyl, oxadiazinyl, oxazepinyl,
oxadiazepinyl, thiadiazolyl, thiazinyl, indolyl, isoindolyl,
benzofuryl, benzothienyl, indazolyl, quinolinyl, isoquinolinyl,
quinoxalinyl, quinazolinyl, benzoxazolyl, benzothiazolyl,
benzimidazolyl, and the like can mentioned.
[0190] As "non-aromatic heterocyclic group", for example, 5 to 14
membered mono-cyclic or bi-cyclic non-aromatic heterocyclic group
containing 1 to 4 heteroatoms selected from nitrogen atom, sulfur
atom and oxygen atom other than carbon atoms as an annular atom can
be mentioned. Specifically, pyrrolidinyl, pyrazolidinyl,
piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl,
homopiperidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl,
imidazolinyl, tetrahydrofuryl, dihydrofuryl, tetrahydrothienyl,
dihydrothienyl, tetrahydropyridyl, dihydrobenzofuryl,
dihydrobenzothienyl, and the like can be mentioned.
[0191] As "alkylthio", for example, straight or branched alkylthio
having 1 to 8 carbon atom, preferably 1 to 4 carbon atoms can be
mentioned, and specifically, methylthio, ethylthio, propylthio,
butylthio, and the like can be mentioned.
[0192] Aryl in "aryloxy" has the same meaning as in the above
"aromatic hydrocarbon group", and phenyl is particularly preferred.
As a specific example for "aryloxy", phenyloxy, naphthyloxy, and
the like can be mentioned.
[0193] Heteroaryl in "heteroaryloxy" has the same meaning as in the
above "aromatic heterocyclic group", and 5 to 6-membered monocyclic
aromatic heterocyclic group containing 1 to 4 heteroatoms selected
from nitrogen atom, sulfur atom and oxygen atom other than carbon
atoms as an annular atom is particularly preferred. As a specific
example for "heteroaryloxy", pyridyloxy, pyrimidinyloxy,
pyrazyloxy, and the like can be mentioned.
[0194] As "cycloalkyloxy", for example, cycloalkyloxy having 3 to 8
carbon atoms, preferably 3 to 6 carbon atoms can be mentioned, and
specifically, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy,
cyclohexyloxy, cycloheptyloxy, and the like can be mentioned.
[0195] As "cycloalkylalkoxy", the above "alkoxy" substituted with
the above "cycloalkyl" can be mentioned, and specifically,
cyclopropylmethoxy, cyclopropylethoxy, cyclobutylmethoxy,
cyclopentylmethoxy, cyclohexylmethoxy, cycloheptylmethoxy, and the
like can be mentioned.
[0196] As "aralkyloxy", for example, the above "alkoxy" substituted
with the above "aromatic hydrocarbon group" can be mentioned, and
specifically, benzyloxy, phenethyloxy, 1-naphthylmethoxy,
2-naphthylmethoxy, and the like can be mentioned.
[0197] As "aralkyloxycarbonyl", for example, the above
"alkoxycarbonyl" substituted with the above "aromatic hydrocarbon
group" can be mentioned, and specifically benzyloxycarbonyl,
phenethyloxycarbonyl, 1-naphthylmethoxycarbonyl,
2-naphthylmethoxycarbonyl, and the like can be mentioned.
[0198] As "alkyl substituted with non-aromatic heterocycle", for
example, the above "alkyl" substituted with the above "non-aromatic
heterocyclic group" can be mentioned, and specifically,
pyrrolidinomethyl, piperidinoethyl, morpholinomethyl,
morpholinoethyl, piperidinomethyl, piperidinoethyl, and the like
can be mentioned.
[0199] As "carbonyl substituted with non-aromatic heterocycle", for
example, carbonyl substituted with the above "non-aromatic
heterocyclic group" can be mentioned, and specifially,
piperidinocarbonyl, morpholinocarbonyl, piperidinocarbonyl, and the
like can be mentioned.
[0200] As "6-membered monocyclic aromatic heterocyclic ring" in
ring A, for example, 6-membered monocyclic aromatic heterocyclic
ring containing 1 to 4 nitrogen atoms other than carbon atom as an
annular atom can be mentioned, and specifically, pyridine,
pyrazine, pyrimidine, pyridazine, triazine, and tetrazine can be
mentioned. Among them, 6-membered monocyclic aromatic heterocyclic
ring containing 1 to 2 nitrogen atoms other than carbon atom as an
annular atom can be preferably mentioned. Of these, pyridine,
pyrazine, pyrimidine, and pyridazine are preferred, pyridine and
pyrazine are more preferred, and pyridine is particularly
preferred.
[0201] As a substituent group of "benzene which may be substituted"
and "6-membered monocyclic aromatic heterocycle which may be
substituted" in Ring A, for example, 1 to 3 alkyls can be
mentioned, and when 2 or more alkyls are present, the substituent
groups may be same or different. As a particularly preferred
substituent group, methyl can be mentioned.
[0202] As "6-membered monocyclic aromatic heterocycle" in ring B,
B.sup.1, B.sup.2 and B.sup.3, for example, 6-membered monocyclic
aromatic heterocycle containing 1 to 4 nitrogen atoms other than
carbon atom as an annular atom can be mentioned, and specifically,
pyridine, pyrazine, pyrimidine, pyridazine, triazine, and tetrazine
can be mentioned. Among them, 6-membered monocyclic aromatic
heterocycle containing 1 to 2 nitrogen atoms other than carbon atom
as an annular atom can be preferably mentioned. Of these, pyridine,
pyrazine, pyrimidine and pyridazine are preferred, and pyridine and
pyrimidine are particularly preferred.
[0203] As a substituent group of "benzene which may be substituted"
and "6-membered monocyclic aromatic heterocycle which may be
substituted" in ring B and ring B.sup.1, for example, alkyl,
halogen atom, and cyano can be mentioned, and 1 to 3 of these
substituent groups may be present. When 2 or more substituent
groups are present, the substituent groups may be same or
different. As a particularly preferred substituent group, methyl,
fluorine atom, chlorine atom, and cyano can be mentioned.
[0204] As a substituent group of "benzene which may be substituted"
and "6-membered monocyclic aromatic heterocycle which may be
substituted" in ring B.sup.2, for example, a group selected from
halogen atom and cyano can be mentioned. 1 to 3 of these
substituent groups may be present, and when 2 or more substituent
groups are present, the substituent groups may be same or
different. As a particularly preferred substituent group, fluorine
atom, chlorine atom, and cyano can be mentioned.
[0205] As a preferred embodiment of ring A-ring B, ring
A-ringB.sup.1, and ring A-ringB.sup.2, groups represented by the
formula as below can be mentioned:
##STR00011##
(wherein G.sub.1, G.sub.2 and G.sub.3 represents CH or nitrogen
atom.)
[0206] As "aromatic heterocyclic group" in ring C, the above
"aromatic heterocyclic group" can be mentioned, and 5 to 6-membered
monocyclic aromatic heterocyclic group containing 1 to 3
heteroatoms selected from nitrogen atom, sulfur atom and oxygen
atom other than carbon atom as an annular atom can be preferably
mentioned. Of these, pyridyl, pyrimidinyl, pyrazolyl, thienyl,
isoxazolyl, oxazolyl, thiazolyl, oxadiazolyl, and triazolyl are
preferred, pyridyl, pyrimidinyl, thienyl, thiazolyl, oxadiazolyl,
and oxazolyl are more preferred, and thienyl is particularly
preferred.
[0207] As ring C, "aromatic hydrocarbon group" is preferred.
[0208] As "alkyl" in Y, Y.sup.a, Y.sup.b, Y.sup.A, Y.sup.B,
Y.sup.C, and Y.sup.D, a group which has 2 substituent groups
(R.sup.5 and R.sup.6) on the same carbon atom of alkyl, and wherein
the 2 substituent groups forms a ring together with the adjacent
carbon atom is included. As such a group, for example, a group
represented by the formula as below can be mentioned:
##STR00012##
(wherein Alk.sup.3 and Alk.sup.4 are same or different, and each
represent alkylene, n represents an integer from 0 to 1, and
R.sup.5 and R.sup.6 each represent hydrogen or alkyl, or R.sup.5
and R.sup.6 represent a group which forms cycloalkane together with
the adjacent carbon atom. Further, a bond at the right end
represents a bond to X, X.sup.A, X.sup.B, X.sup.C, and
X.sup.D.)
[0209] As a preferred specific example of "alkyl" in Y, Y.sup.a,
Y.sup.b, Y.sup.A, Y.sup.B, Y.sup.C, and Y.sup.D, following groups
can be mentioned:
##STR00013##
(wherein a bond at the right end represents a bond to X, X.sup.A,
X.sup.B, X.sup.C, and X.sup.D.)
[0210] In particular, following groups are preferred:
##STR00014##
[0211] (wherein a bond at the right end represents a bond to X,
X.sup.A, X.sup.B, X.sup.C, and X.sup.D.)
[0212] As a substituent group of "alkyl which may be substituted"
in Y and Y.sup.a, for example, aminocarbonyl which may be
substituted with alkyl which may be substituted with 1 to 3
hydroxys, and carboxy can be mentioned, and 1 to 3 of these
substituent groups may be present. When 2 or more substituent
groups are present, the substituent groups may be same or
different. Among these, as a preferred substituent group, carboxy
can be mentioned.
[0213] As a substituent group of "alkyl which may be substituted"
in Y.sup.b, for example, carboxy can be mentioned.
[0214] As a substituent group of "cycloalkyl which may be
substituted" in Y.sup.a, for example, carboxyalkyl can be
mentioned, and 1 to 3 of the substituent groups may be present. As
a specific example of the substituent group, carboxymethyl and the
like can be mentioned.
[0215] As a substituent group of "cycloalkyl which may be
substituted" in Y and Y.sup.b, for example, carboxyalkyl, carboxy,
alkoxyalkyl, and aminocarbonyl can be mentioned, and 1 to 3 of
these substituent groups may be present. When 2 or more substituent
groups are present, the substituent groups may be same or
different. As a preferred substituent group, carboxyalkyl, carboxy,
and alkoxyalkyl can be mentioned.
[0216] As "cycloalkyl" in Y.sup.b, cycloalkyl containing 3 to 6
carbon atoms is preferred, and in particular, cyclohexyl is
preferred.
[0217] As Y.sup.b, "alkyl which may be substituted" is
preferred.
[0218] As a substituent group of "alkyl which may be substituted"
in R.sup.1, for example, 1 to 6 halogen atoms can be mentioned, and
when 2 or more substituent groups are present, the substituent
groups may be same or different. As a particularly preferred
substituent group, fluorine atom can be mentioned. As a specific
example of "alkyl which may be substituted", difluoromethyl,
trifluoromethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl,
and the like can be mentioned, and in particular, trifluoromethyl
is preferred.
[0219] As "halogen atom" represented by R.sup.1, chlorine atom is
particularly preferred.
[0220] As "alkyl" represented by R.sup.1, alkyl containing 1 to 3
carbon atoms is preferred, and in particular, methyl is
preferred.
[0221] As "alkoxy" represented by R.sup.1, alkoxy containing 1 to 3
carbon atoms is preferred, and in particular, methoxy is
preferred.
[0222] As a substituent group of "alkyl which may be substituted"
in R.sup.3 and R.sup.4, 1 to 6 halogen atoms can be mentioned,
respectively, and when 2 or more substituent groups are present,
the substituent groups may be same or different. In particular,
fluorine atom is preferred. As a specific example of "alkyl which
may be substituted", difluoromethyl, trifluoromethyl,
2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl, and the like can
be mentioned, and in particular, trifluoromethyl is preferred.
[0223] As a substituent group of "alkoxy which may be substituted"
in R.sup.3 and R.sup.4, alkoxy and 1 to 6 halogen atoms can be
mentioned, respectively, and when 2 or more substituent groups are
present, the substituent groups may be same or different. In
particular, fluorine atom is preferred. As a specific example of
"alkoxy which may be substituted", difluoromethoxy,
trifluoromethoxy, 2,2,2-trifluoroethoxy,
2,2,3,3,3-pentafluoropropoxy, and the like can be mentioned, and in
particular, difluoromethoxy and trifluoromethoxy are preferred.
[0224] As a substituent group of "alkyl which may be substituted"
in R.sup.2 and R.sup.2b, for example, 1 to 6 halogen atoms can be
mentioned, and when 2 or more substituent groups are present, the
substituent groups may be same or different. As a particularly
preferred substituent group, fluorine atom can be mentioned. As a
specific example of the group, trifluoromethyl,
2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl, and the like can
be mentioned.
[0225] As a substituent group of "alkoxy which may be substituted"
in R.sup.2 and R.sup.2b, for example, 1 to 6 halogen atoms can be
mentioned, and when 2 or more substituent groups are present, the
substituent groups may be same or different. In particular,
fluorine atom is preferred. As a specific example of the group,
trifluoromethoxy, 2,2,2-trifluoroethoxy,
2,2,3,3,3-pentafluoropropoxy, and the like can be mentioned.
[0226] As a substituent group of "cycloalkyl which may be
substituted" in R.sup.2 and R.sup.2b, for example, alkyl which may
be substituted with 1 to 7 halogens can be mentioned, and when 2 or
more substituent groups are present, the substituent groups may be
same or different. As a specific example of the group,
1-trifluoromethylcyclopropyl, 1-trifluoromethylcyclobutyl,
1-trifluoromethylcyclohexyl, 1-trifluoromethylcyclohexyl, and the
like can be mentioned.
[0227] As a substituent group of "aromatic hydrocarbon group which
may be substituted" in R.sup.2 and R.sup.2b, for example, 1 to 3
alkoxys can be mentioned, and when 2 or more substituent groups are
present, the substituent groups may be same or different. As a
specific example of the group, 4-methoxyphenyl, 3-methoxyphenyl,
2-methoxyphenyl, 3,4-dimethoxyphenyl, and the like can be
mentioned.
[0228] As a substituent group of "non-aromatic heterocyclic group
which may be substituted" in R.sup.2 and R.sup.2b, for example, 1
to 3 halogen atoms can be mentioned, and when 2 or more substituent
groups are present, the substituent groups may be same or
different. As a specific example of the group, 4-fluoropiperidino,
4,4-difluoropiperidino, and the like can be mentioned.
[0229] As a substituent group of "aryloxy which may be substituted"
in R.sup.2 and R.sup.2b, for example, a group selected from halogen
atom and cyano can be mentioned. 1 to 3 of the substituent groups
may be present, and when 2 or more groups are present, the
substituent groups may be same or different. As a specific example
of the group, 4-fluorophenyloxy, 2,4-difluorophenyloxy,
3,4-difluorophenyloxy, 4-cyanophenyloxy, and the like can be
mentioned.
[0230] As a substituent group of "heteroaryloxy which may be
substituted" in R.sup.2 and R.sup.2b, for example, 1 to 3 alkyls
can be mentioned, and when 2 or more substituent groups are
present, the substituent groups may be same or different. As a
specific example of the group, 6-methylpyridin-2-yloxy,
6-methylpyrimidin-2-yloxy, and the like can be mentioned.
[0231] Since the compound of the present invention has a basic
group and an acidic group in the molecule, as a pharmaceutically
acceptable salt thereof, an acid addition salt (for example,
inorganic acid salt such as hydrochloride, sulfate, phosphate,
hydrobromide; and organic acid salt such as acetate, fumarate,
maleate, oxalate, citrate, methanesulfonate, benzenesulfonate,
toluenesulfonate), and a salt with a base (for example, alkali
metal salt such as sodium salt, potassium salt; alkali earth metal
salt such as calcium salt; organic base salt such as triethylamine
salt; and amino acid salt such as lysine salt; and the like) can be
mentioned.
[0232] In the compound of the present invention, an optical isomer
based on asymmetric carbon may exist, and the compound of the
present includes any isomer thereof and a mixture thereof. Further,
if the compound of the present invention has a cycloalkanediyl, a
cis form and a trans form may be present, and in the compound of
the present invention, a tautomer based on an unsaturated bond such
as carbonyl may be present. The compound of the present invention
includes any isomer thereof and any mixture thereof.
[0233] Further, in the compound of the present invention a tautomer
may exist as shown by formulae as below due to hydrogen ion
transfer in an aromatic heterocyclic ring. Even when the compound
of the present invention is represented by one of chemical
structure, any tautomer thereof and any mixture thereof are
included.
##STR00015##
[0234] Although the compound of the present invention or a
pharmaceutically acceptable salt thereof can be also prepared by
the process as below.
[0235] A process for preparing Compound (1) of the invention is
explained below by using Compound (1-A) and Compound (1-B) included
in the Compound (1), and Compound (1) can be prepared in a manner
similar to these processes.
[Method A]
[0236] Compound (1-A) can be prepared by the process as below:
##STR00016##
(wherein HAL.sub.1 represents halogen atom (such as chlorine atom
and bromine atom), and the other symbols have the same meaning as
above.)
Step I:
[0237] The reaction of Compound (2) with hydroxylamine can be
carried out, for example, in an appropriate solvent, according to
the process as described in U.S. Pat. No. 5,576,447 and the
like.
[0238] As the solvent, alcohols such as methanol and ethanol,
ethers such as tetrahydrofuran and 1,4-dioxane, water, or a mixture
thereof can be used.
[0239] The reaction time is usually 3 to 16 hours, preferably 4 to
6 hours. The reaction temperature is usually 5 to 100.degree. C.,
preferably 25 to 80.degree. C.
[0240] According to an ordinary method, the obtained product is
treated with acetic acid-acetic anhydride, and subjected to a
hydrogenation reaction in an appropriate solvent in the presence of
palladium catalyst under hydrogen atmosphere to obtain Compound (3)
as an acetate salt.
[0241] As the solvent, for example, alcohols such as methanol and
ethanol, ethers such as tetrahydrofuran and 1,4-dioxane, acetic
acid, or a solvent mixture thereof can be used.
[0242] As the palladium catalyst, for example, a catalyst such as
palladium carbon, palladium black and palladium chloride can be
used.
[0243] The reaction time differs depending on the catalyst, the
solvent, and the like to be used, and is usually 30 minutes to 18
hours, preferably 30 minutes to 8 hours. The reaction temperature
is usually 10 to 100.degree. C., preferably 25 to 75.degree. C.
[0244] Meanwhile, trialkylsilane such as triethylsilane can be used
as a hydrogen source instead of hydrogen in the above hydrogenation
reaction.
[0245] Further, Compound (3) can be prepared by reacting Compound
(2) with an alkoxy alkali metal in an appropriate solvent, followed
by reacting with ammonia source.
[0246] As the solvent, alcohols such as methanol and ethanol can be
used.
[0247] As the alkoxy alkali metal, sodium methylate, sodium
ethylate, potassium methylate, and the like can be used.
[0248] As the ammonia source, an ammonium halide such as ammonium
chloride and ammonium bromide, an organic ammonium salt such as
ammonium acetate and ammonium propionate, ammonia and the like can
be used.
Step II:
[0249] Compound (1-A) can be prepared, for example, by subjecting
Compound (3) and Compound (4) to a cyclization reaction in an
appropriate solvent in the presence of base according to a method
as described in I. M. Mallick et al., Journal of the American
Chemical Society, 106(23), 7252-7254, 1984, and the like.
[0250] As the solvent, alcohols such as methanol and ethanol,
amides such as N, N-dimethyformamide and N-methylpyrrolidone,
halogenated hydrocarbons such as methylene chloride and chloroform,
tetrahydrofuran, acetonitrile, water, or a solvent mixture thereof
can be used.
[0251] As the base, potassium hydrogen carbonate, potassium
carbonate, sodium ethylate, and the like can be used.
[0252] The reaction time differs depending on the base, the
solvent, and the like to be used, and is usually 40 minutes to 18
hours, preferably 5 hour to 12 hours. The reaction temperature is
usually 18 to 100.degree. C., preferably 50 to 80.degree. C.
[0253] Compound (1-A) can also be prepared by reacting, in an
appropriate solvent in the presence of acid, a product obtained by
reacting Compound (3) and Compound (4) in the above method.
[0254] As the acid, for example, hydrochloric acid, sulfuric acid,
acetic acid, trifluoroacetic acid, p-toluenesulfonic acid,
camphorsulfonic acid, and the like can be used.
[0255] As the solvent, for example, aromatic hydrocarbons such as
benzene and toluene, halogenated hydrocarbons such as chloroform
and 1,2-dichloroethane, ethers such as tetrahydrofuran and
1,2-dimethoxyethane, organic acids such as formic acid and acetic
acid, or a solvent mixture thereof can be used.
[0256] The reaction time differs depending on the acid, the
solvent, and the like to be used, and is usually 1 hour to 48
hours, preferably 4 hours to 8 hours. The reaction temperature is
usually 50 to 100.degree. C., preferably 70 to 90.degree. C.
[Method B]
[0257] Compound (1-A) can also be prepared by the process as
below:
##STR00017##
(wherein Lv.sup.1 represents B(OH).sub.2, or
##STR00018##
[0258] HAL.sub.2 represents halogen atom (such as chlorine atom and
bromine atom), PG.sub.1 represents amino protective group
(preferably, substituted alkyl (such as
2-(trimethylsilyl)ethoxymethyl and benzyl)), and the other symbols
have the same meanings as the above.)
Step I;
[0259] Compound (7) can be prepared by subjecting Compound (5) and
Compound (6) to Suzuki coupling reaction (for example, a reaction
as described in Advanced Organic Chemistry Part B (F. A. Carey
& R. J. Sundberg, Springer) and the like) in an appropriate
solvent in the presence of a catalyst and a base.
[0260] As the catalyst, palladium chloride, palladium acetate,
dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium
(PdCl.sub.2(dppf)), tetrakistriphenylphosphine palladium and the
like can be used, and if necessary, a ligand such as
1,1'-bis(diphenylphosphino)ferrocene,
2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (S-PHOS),
2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl
(X-PHOS) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene
(Xantphos) can also be added.
[0261] As the base, an alkali metal such as sodium carbonate,
potassium carbonate, potassium acetate, potassium phosphate, sodium
hydroxide, and cesium carboate, and the like can be used.
[0262] As the solvent, amides such as N, N-dimethyformamide, ethers
such as tetrahydrofuran, 1,4-dioxane and dimethoxyethane, aromatic
hydrocarbons such as benzene and toluene, water, and a solvent
mixture thereof can be used.
[0263] The reaction time differs depending on the amount or the
kind of the reagent, the catalyst, the base, or the reaction
solvent to be used, and the reaction temperature, and is usually 2
to 48 hours, preferably 5 to 12 hours.
[0264] The reaction temperature is from room temperature to
150.degree. C., preferably 60 to 120.degree. C.
Step II:
[0265] Compound (1-A) can be prepared by deprotecting Compound
(7).
[0266] The deprotection reaction of Compound (7) can be carried
out, for example, when PG.sub.1 is 2-(trimethylsilyl)ethoxymethyl,
by treating Compound (7) with an acid (such as hydrochloric acid,
trifluoroacetic acid and methanesulfonic acid) in an appropriate
solvent (alcohols such as methanol and ethanol, water, a solvent
mixture thereof, and the like), or by reacting Compound (7) with
tetra-n-butylammonium fluoride in an appropriate solvent (ethers
such as tetrahydrofuran, halogenated hydrocarbons such as methylene
chloride, and the like) to yield Compound (1-A). Further, for
example, when PG.sub.1 is benzyl, Compound (7) is subjected to a
hydrogenation reaction in an appropriate solvent (alcohols such as
methanol and ethanol, and the like) in the presence of palladium
catalyst (such as palladium carbon and palladium hydroxide) under
hydrogen atmosphere to prepare Compound (1-A).
[0267] Further, Compound (1-A) can also be prepared by carrying out
a similar method to the above using the compounds represented by
formulae as below:
##STR00019##
(wherein each symbol has the meaning as the above), (hereinafter,
referred to as Compound (5a) and Compound (6a)) instead of Compound
(5) and Compound (6), respectively.
[Method C]
[0268] Compound (1-A) wherein X is --O-- (hereinafter referred to
as Compound (1-A-a)) can be prepared by the process as below:
##STR00020##
(wherein each symbol has the same meaning as the above.)
Step I:
[0269] Compound (10) can be prepared by subjecting Compound (8) and
Compound (9) to Mitsunobu reaction (for example, a reaction as
described in Advanced Organic Chemistry Part B (F. A. Carey &
R. J. Sundberg, Springer), Okuda, M.; Tomioka, K.; Tetrahedron Lett
[TELEAY] 1994, 35 (26), 4585-4586, and the like) in an appropriate
solvent in the presence of azodicarboxylates and phosphines.
[0270] As the azodicarboxylates, diethyl azodicarboxylate,
di-t-butyl azodicarboxylate, 1,1'-(azodicarbonyl)dipiperidine, and
the like can be used.
[0271] As the phosphines, tri-aryl phosphines such as
triphenylphosphine, tri-alkylphosphines such as
tri-n-butylphosphine, and the like can be used.
[0272] As the solvent, for example, ethers such as tetrahydrofuran,
1,4-dioxane and diethylether, aromatic hydrocarbons such as
benzene, toluene and xylene, halogenated hydrocarbons such as
methylene chloride, 1,2-dichloroethane and chloroform, or a solvent
mixture thereof can be used.
[0273] The reaction time differs depending on the reagent, the
solvent, and the like to be used, and is usually 30 minutes to 24
hours, preferably 3 to 12 hours. The reaction temperature is
usually 5.degree. C. to 150.degree. C., preferably room temperature
to 80.degree. C.
Step II:
[0274] The deprotection reaction of Compound (10) can be carried
out in a manner similar to Step II of Method B.
[Method D]
[0275] Compound (1-A) wherein X is a single bond and Y.sup.a is
cycloalkyl which may be substituted (hereinafter, referred to as
Compound (1-A-b)) can be prepared by the process as below:
##STR00021##
(wherein a group:
##STR00022##
[0276] represents cycloalkenyl which may be substituted, Y.sup.2
represents cycloalkyl which may be substituted, Lv.sup.2 represents
halogen atom (such as chlorine atom and bromine atom) or
trifluoromethanesulfonyloxy group, and Lv.sup.3 represents
B(OH).sub.2 or
##STR00023##
[0277] and the other symbols have the same meanings as the
above.)
Step I:
[0278] Compound (13) can be prepared by a coupling reaction of
Compound (11) with Compound (12), which can be carried out in a
manner similar to Step I of Method B.
Step II:
[0279] Compound (14) can be prepared by subjecting Compound (13) to
a hydrogenation reaction in an appropriate solvent in the presence
of a palladium catalyst under hydrogen atmosphere.
[0280] As the solvent, alcohols such as methanol and ethanol,
ethers such as tetrahydrofuran and 1,4-dioxane, or a solvent
mixture thereof can be used.
[0281] As the palladium catalyst, a catalyst such as palladium
carbon and palladium black can be used.
[0282] The reaction time differs depending on the catalyst, the
solvent, and the like to be used, and is usually 1 hour to 24
hours, preferably 1 hour to 12 hours. The reaction temperature is
usually 50 to 100.degree. C., preferably 60 to 100.degree. C.
Step III:
[0283] The deprotection reaction of Compound (14) can be carried
out in a manner similar to Step II of Method B.
[Method E]
[0284] Compound (1-A) wherein R.sup.1 is halogen (hereinafter,
referred to as Compound (1-A-d)) and Compound (1-A) wherein R.sup.1
is alkyl (hereinafter, referred to as Compound (1-A-e)) can be
prepared by the process as below:
##STR00024##
(wherein HAL.sub.3 represents halogen atom (such as chlorine atom
and bromine atom), and R.sup.1a represents alkyl, and Lv.sup.4
represents B(OH).sub.2 or
##STR00025##
and the other symbols have the same meaning as above.)
Step I:
[0285] Compound (1-A-d) can be prepared by reacting Compound
(1-A-c) with a halogenating agent in an appropriate solvent, if
necessary, in the presence of base.
[0286] As the halogenating agent, N-chlorosuccinimide,
N-bromosuccinimide, and the like can be used.
[0287] As the solvent, a halogenated hydrocarbon such as chloroform
and methylene chloride, N, N-dimethyformamide, acetonitrile,
ethanol, and the like can be used.
[0288] As the base, imidazole, triethylamine, and the like can be
used.
[0289] The reaction time differs depending on the reagent, the
solvent, and the like to be used, and is usually 1 hour to 22
hours, preferably 2 hours to 15 hours. The reaction temperature is
usually 0.degree. C. to 60.degree. C., preferably room temperature
to 50.degree. C.
Step II:
[0290] The reaction of Compound (1-A-d) with Compound (15) can be
carried out in a manner similar to Step I of Method B.
[Method F]
[0291] Compound (2) wherein X is --O-- (hereinafter, referred to as
Compound (2a)) can also be prepared by the process as below:
##STR00026##
(wherein HAL.sub.4 and HAL.sub.5 represent halogen atom (such as
chlorine atom and bromine atom), and Lv.sup.5 represents
B(OH).sub.2 or
##STR00027##
and the other symbols have the same meanings as the above.)
Step I:
[0292] The coupling reaction of Compound (16) with Compound (9) can
be carried out in a manner similar to Step I of Method C.
Step II:
[0293] Compound (18) can be prepared by reacting Compound (17) with
a boronic acid ester in an appropriate solvent in the presence of a
palladium catalyst, a ligand and a base.
[0294] As the solvent, ethers such as 1,4-dioxane, dimethyl
sulfoxide, aromatic hydrocarbons such as toluene, and the like can
be used.
[0295] As the palladium catalyst, palladium acetate,
dichloro[1,1'-bis(di phenylphosphino)ferrocene]palladium
(PdCl.sub.2(dppf)) and the like can be used.
[0296] As the ligand,
2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (S-PHOS),
2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl
(X-PHOS), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene
(Xantphos), and the like can be used.
[0297] As the base, potassium acetate, potassium phosphate, and the
like can be used.
[0298] As the boronic acid ester, bis(pinacolato)diboron,
trialkoxyboron, and the like can be used.
[0299] The reaction time differs depending on the catalyst, the
solvent, and the like to be used, and is usually 1 hour to 24
hours, preferably 2 hours to 12 hours. The reaction temperature is
usually 50 to 130.degree. C., preferably 60 to 100.degree. C.
Step III:
[0300] The coupling reaction of Compound (18) with Compound (19)
can be carried out in a manner similar to Step I of Method B.
[Method G]
[0301] Compound (8), and Compound (11a) which is Compound (11)
wherein Lv.sup.2 is trifluoromethanesulfonyloxy can be prepared by
the process as below:
##STR00028##
[0302] (wherein PG.sub.2 represents a hydroxyl group-protective
group (preferably, substituted alkyl (such as benzyl)), Lv.sup.6
represents B(OH).sub.2, or
##STR00029##
and each symbol has the same meaning as above.)
Step I:
[0303] The coupling reaction of Compound (6) with Compound (20) can
be carried out in a manner similar to Step I of Method B.
Step II:
[0304] Compound (8) can be prepared by deprotecting PG.sub.2 of
Compound (21).
[0305] The deprotecting reaction of PG.sub.2 can be carried out,
for example, when PG.sub.2 is a benzyl group, by subjecting
Compound (21) to a hydrogenation reaction in an appropriate solvent
(alcohols such as methanol and ethanol) in the presence of a
palladium catalyst (such as palladium carbon and palladium
hydroxide) under hydrogen atmosphere to prepare Compound (8).
Step III:
[0306] Compound (11a) can be prepared by reacting Compound (8) with
trifluoromethanesulfonic anhydride in an appropriate solvent
(halogenated hydrocarbons such as methylene chloride and
chloroform, ethers such as tetrahydrofuran and diethylether, and
the like) in the presence of a base (such as triethylamine,
N,N-diisopropylethylamine and 2,6-lutidine) at 0.degree. C. to
25.degree. C. for 1 hour to 8 hours.
[Method H]
[0307] Compound (6) can also be prepared by the process as
below:
##STR00030##
(wherein each symbol has the same meaning as above.)
[0308] Step I and Step II in the present reaction can be carried
out in a manner similar to Step I and Step II of Method A.
Step III:
[0309] Compound (6) can be prepared by protecting the amino group
of Compound (24). For example, when PG.sub.1 is
2-(trimethylsilyl)ethoxymethyl group, Compound (6) can be prepared
by reacting Compound (24) with 2-(trimethylsilyl)ethoxymethyl
chloride in an appropriate solvent in the presence of a base.
[0310] As the solvent, for example, an aprotic polar solvent such
as N, N-dimethy formamide, N,N-dimethylacetamide and
N-methylpyrrolidone can be used.
[0311] As the base, for example, an alkali metal hydride (such as
sodium hydride and lithium hydride), an alkali metal carbonate
(such as potassium carbonate) can be used.
[Method I]
[0312] Compound (6) wherein R.sup.1 is hydrogen (hereinafter,
referred to as Compound (6a)) can be prepared by the process as
below:
##STR00031##
(wherein each symbol has the same meaning as above.)
Step I:
[0313] Compound (27) can be prepared by reacting Compound (25) with
Compound (26) and ammonia in an appropriate solvent.
[0314] As the solvent, an alcoholic solvent such as methanol and
ethanol, water, and the like can be used.
[0315] The reaction time is usually 1 hour to 24 hours, preferably
5 hours to 12 hours. The reaction temperature is usually 5.degree.
C. to 60.degree. C., preferably room temperature to 40.degree.
C.
Step II:
[0316] The present reaction can be carried out in a manner similar
to Step III of Method H.
[Method J]
[0317] Compound (27) can also be prepared by the process as
below:
##STR00032##
(wherein HAL.sub.6 and HAL.sub.7 are the same or different and
represent a halogen atom (such as chlorine atom, bromine atom and
iodine atom).)
[0318] Compound (27) can be prepared by reacting Compound (25) with
Compound (28) and ammonia in an appropriate solvent in the presence
of a base according to a method as described in J. J. Baldwin et
al., Journal of Medicinal Chemistry, 29(6), 1065-1080, 1986 and the
like.
[0319] As the solvent, alcohols such as methanol and ethanol,
water, and the like can be used.
[0320] As the base, alkali metal acetate (for example, sodium
acetate) and the like can be used.
[0321] The present reaction can be carried out by stirring Compound
(28) in an aqueous solvent in the presence of a base at 90 to
100.degree. C. for 30 minutes to 1 hour, and then adding Compound
(25) and ammonia water to the reaction system under cooling, and
further stirring under ice-cooling to 50.degree. C. for 1 day to 2
days. The reaction is preferably carried out at room temperature to
40.degree. C.
[Method K]
[0322] Compound (4) can also be prepared by the process as
below:
##STR00033##
(wherein each symbol has the same meaning as above.)
[0323] Compound (4) can be prepared by reacting Compound (29) with
a halogenating agent in an appropriate solvent (for example,
halogenated hydrocarbons such as methylene chloride).
[0324] As the halogenating agent, for example, N-bromosuccinimide,
N-chlorosuccinimide, copper bromide, hydrobromic acid,
benzyltrimethylammonium tribromide, and the like can be
mentioned.
[Method L]
[0325] Compound (4) wherein R.sup.1 is hydrogen (hereinafter,
referred to as Compound (4a)) can also be prepared by the process
as below:
##STR00034##
(wherein each symbol has the same meaning as above.)
[0326] Compound (4a) can be prepared by reacting Compound (30) with
oxalyl chloride in an appropriate solvent, and reacting with
trimethylsilyldiazomethane, then by subjecting to a halogenation in
an appropriate solvent.
[0327] As the solvent for the reaction of Compound (30) with oxalyl
chloride, halogenated hydrocarbon such as chloroform and methylene
chloride, ethers such as tetrahydrofuran, and the like can be
used.
[0328] The present reaction can be carried out by adding a
catalystic amount of N, N-dimethyformamide at -20 to 40.degree. C.,
preferably under ice-cooling to room temperature.
[0329] As the solvent for the reaction with
trimethylsilyldiazomethane, acetonitrile, ethers such as
tetrahydrofuran, and halogenated hydrocarbon such as chloroform and
methylene chloride and the like can be used.
[0330] The present reaction can be carried out at -20 to 40.degree.
C., preferably under ice-cooling to room temperature.
[0331] The halogenation can be carried out in a manner similar to
the halogenation of Method K.
[Method M]
[0332] A compound of the general formula (B) wherein X.sup.B is a
single bond, and Y.sup.B is phenyl which may be substituted
(hereinafter, referred to as Compound (B1)) can be prepared by the
process as below:
##STR00035##
(wherein X.sup.B1 represents a single bond, Y.sup.B1 represents
phenyl which may be substituted, Lv.sup.7 represents a halogen atom
(such as chlorine atom and bromine atom), B(OH).sub.2 or
##STR00036##
and the other symbols have the same meanings as above.
Step I:
[0333] (1) When Lv.sup.7 represents B(OH).sub.2 or
##STR00037##
Compound (33) can be prepared by reacting Compound (31) with
Compound (32) in an appropriate solvent in the presence of a
catalyst such as a copper catalyst, and a base.
[0334] As the solvent, halogenated hydrocarbons such as methylene
chloride and 1,2-dichloroethane, aromatic hydrocarbons such as
toluene, polar solvent such as acetonitrile, dimethylformamie and
dimethylsulfoxide, and the like can be used.
[0335] As the catalyst, a copper catalyst such as copper acetate,
and the like can be used.
[0336] As the base, organic base such as triethylamine and
pyridine, and the like can be used.
[0337] Further, if necessary, a dehydrating agent such as molecular
sieve can be used.
[0338] The reaction time differs depending on the reagent, the
solvent, and the like to be used, and is usually 12 hours to 144
hours, preferably 24 hours to 48 hours. The reaction temperature is
usually 20.degree. C. to 90.degree. C., preferably 20.degree. C. to
40.degree. C.
(2) When Lv.sup.7 is halogen, Compound (33) can be prepared by
reacting Compound (31) with Compound (32) in an appropriate solvent
in the presence of a base, and if necessary in the presence of a
palladium catalyst and a ligand.
[0339] As the solvent, ethers such as tetrahydrofuran, 1 4-dioxane
and dimethoxyethane, aromatic hydrocarbons such as benzene and
toluene, halogenated hydrocarbons such as methylene chloride and
1,2-dichloroethane, water, N, N-dimethy formamide,
dimethylsulfoxide, or a solvent mixture thereof can be used.
[0340] As the base, an inorganic base such as sodium carbonate,
potassium carbonate, potassium acetate, potassium phosphate, sodium
hydroxide and cesium carbonate, an organic base such as
triethylamine, N,N-diisopropylethylamine,
1,8-diazabicyclo[5.4.0]undeca-7-en (DBU) and N-methylmorpholine,
sodium tert-butoxide, and the like can be used.
[0341] As the catalyst, palladium chloride, palladium acetate,
dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium
(PdCl.sub.2(dppf)), tetrakistriphenylphosphinepalladium and the
like can be used, and if necessary, a ligand such as
1,1'-bis(diphenylphosphino)ferrocene,
2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (S-PHOS),
2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl
(X-PHOS), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene
(Xantphos),
2-dicyclohexylphosphino-2',6'-di-isopropoxy-1,1'-biphenyl (RuPhos)
and the like can be added.
[0342] The reaction time differs depending on the reagent, the
solvent, and the like to be used, and is usually 1 hour to 24
hours, preferably 3 hours to 15 hours. The reaction temperature is
usually 70.degree. C. to 120.degree. C., preferably 80.degree. C.
to 100.degree. C.
[0343] In the present reaction, the reaction can be accelerated by
microwave irradiation.
Step II:
[0344] Compound (B1) can be prepared by deprotecting Compound (33),
which can be carried out in a manner similar to Step II of Method
B.
[Method N]
[0345] The compound of the general formula (B) or the general
formula (C) (hereinafter, referred to as Compound (X)) can also be
prepared by the process as below:
##STR00038##
(wherein a group:
##STR00039##
represents piperidine, or piperazine which may be substituted with
P and/or Q; B.sup.X, X.sup.X, Y.sup.X, R.sup.1X and R.sup.2X
represent a group comprising B.sup.1 and B.sup.3, X.sup.B and
X.sup.C, Y.sup.B and Y.sup.C, R.sup.1B and hydrogen atom, and
R.sup.2B and R.sup.2C, respectively, and the other symbols have the
same meanings as above.) Step I and Step II in the present reaction
can be carried out in a manner similar to Step I and Step II of
Method M.
[Method O]
[0346] The compound of the general formula (C) wherein X.sup.C is
--O-- or --OCH.sub.2-- and Y.sup.C is phenyl which may be
substituted (hereinafter, referred to as Compound (C1)) can be
prepared by the process as below:
##STR00040##
(wherein Y.sup.C1 represents phenyl which may be substituted, n
represents an integer from 0 to 1, and the other symbols have the
same meanings as above.)
[0347] Step I and Step II of the present reaction can be carried
out in a manner similar to Step I of Method N and Step I of Method
C, and further PG.sub.1 is deprotected to prepare Compound
(C1).
[Method P]
[0348] Compound (34) wherein a group:
##STR00041##
is piperidine, and X is --O-- (hereinafter, referred to as Compound
(34a)) can be prepared by the process as below:
##STR00042##
(wherein each symbol has the same meaning as above.) Compound (34)
can be prepared by subjecting Compound (36) to a reduction
reaction.
[0349] The present reaction can be carried out by reacting Compound
(36) with a reducing agent (such as sodium borohydride) in an
appropriate solvent (for example, alcohols such as methanol and
ethanol, and the like), and then subjecting to a hydrogenation
reaction in the presence of a catalyst (such as palladium carbon)
to prepare Compound (34a).
[Method Q]
[0350] The compound represented by the general formula (D) can be
prepared by the process as below:
##STR00043##
(wherein Lv.sup.8 represents B(OH).sub.2, or
##STR00044##
and the other symbols have the same meanings as above.)
[0351] Step I to Step III of the present reaction can be carried
out in a manner similar to Step I to Step III of Method D.
[Method R]
[0352] Compound (1-B) can be prepared by the process as below:
##STR00045##
(wherein Lv.sup.9 represents B(OH).sub.2 or
##STR00046##
[0353] HAL.sub.8 represents a halogen atom (such as chlorine atom
and bromine atom), PG.sub.3 represents an amino-protective group
(preferably, substituted alkyl (2-(trimethylsilyl)ethoxymethyl,
benzyl, and the like), and the other symbols have the same meanings
as above.)
Step I:
[0354] Compound (42) can be prepared by subjecting Compound (40)
and Compound (41) to Suzuki coupling reaction (for example, a
reaction as described in Advanced Organic Chemistry Part B (F. A.
Carey & R. J. Sundberg, Springer), and the like) in an
appropriate solvent in the presence of a catalyst and a base.
[0355] As the catalyst, palladium chloride, palladium acetate,
[1,1'-bis(diphenylphosphino)ferrocene]palladium (II) dichloride
dichloromethane complex (PdCl.sub.2(dppf)CH.sub.2Cl.sub.2),
tetrakistriphenylphosphinepalladium, and the like can be used, and
if necessary a ligand such as 1,1'-bis(diphenylphosphino)ferrocene,
2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (S-PHOS),
2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl
(X-PHOS), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene
(Xantphos) and the like can be added.
[0356] As the base, an alkali metal such as sodium carbonate,
potassium carbonate, potassium acetate, potassium phosphate, sodium
hydroxide, and cesium carbonate, and the like can be used.
[0357] As the solvent, amides such as N, N-dimethyformamide, ethers
such as tetrahydrofuran, 1,4-dioxane and dimethoxyethane, aromatic
hydrocarbons such as benzene and toluene, water, or a solvent
mixture thereof can be used.
[0358] The reaction time differs depending on the amount or the
kind of the reagent, the catalyst, the base, or the reaction
solvent to be used and the reaction temperature, and is usually 2
to 48 hours, preferably 5 to 12 hours.
[0359] The reaction temperature is room temperature to 150.degree.
C., preferably 60 to 120.degree. C.
Step II:
[0360] Compound (1-B) can be prepared by deprotecting Compound
(42).
[0361] The deprotection reaction of Compound (42) can be carried
out, for example, when PG.sub.3 is 2-(trimethylsilyl)ethoxymethyl,
by treating Compound (42) with an acid (such as hydrochloric acid,
trifluoroacetic acid and methanesulfonic acid) in an appropriate
solvent (such as alcohols such as methanol and ethanol, water, or
solvent mixture thereof) to prepare Compound (1-B). Further,
Compound (1-B) can also be prepared by reacting Compound (42) with
tetra-n-butylammonium fluoride in an appropriate solvent (ethers
such as tetrahydrofuran, or halogenated hydrocarbons such as
methylene chloride and the like).
[0362] Compound (1-B) can also be prepared by carrying out a
similar method to the above using the compounds represented by
following formulae:
##STR00047##
[0363] (wherein each symbol has the same meaning as above,)
(hereinafter, referred to as Compound (40a) and Compound (41a)),
instead of Compound (40) and Compound (41).
[Method S]
[0364] Compound (1-B) wherein R.sup.2b is alkyl which may be
substituted, an aromatic hydrocarbon group which may be
substituted, or cycloalkyl which may be substituted (hereinafter,
referred to as Compound (1-B-a)) can be prepared by the process as
below:
##STR00048##
(wherein R.sup.2b1 represents alkyl which may be substituted, an
aromatic hydrocarbon group which may be substituted, or cycloalkyl
which may be substituted, R.sup.z represents alkyl, and the other
symbols have the same meanings as above.)
Step I:
[0365] Compound (44) can be prepared by (i) reacting Compound (43)
with hydroxylamine followed by treatment with acetic acid-acetic
anhydride and then a hydrogenation, or (ii) reacting Compound (43)
with an alcohol in the presence of an acid, followed by reaction
with ammonia or (iii) by reacting Compound (43) with lithium
hexamethyldisilazane followed by treatment with an acid.
Reaction (i)
[0366] The reaction of Compound (43) with hydroxylamine can be
carried out, for example, in an appropriate solvent, according to a
method as described in U.S. Pat. No. 5,576,447 and the like.
[0367] As the solvent, alcohols such as methanol and ethanol,
ethers such as tetrahydrofuran and 1,4-dioxane, water, and a
solvent mixture thereof can be used.
[0368] The reaction time is usually 3 to 24 hours, preferably 4 to
18 hours. The reaction temperature is usually 5 to 100.degree. C.,
preferably 25 to 80.degree. C.
[0369] Thus obtained product is treated with acetic acid-acetic
anhydride, and subjected to a hydrogenation reaction in an
appropriate solvent in the presence of a palladium catalyst under
hydrogen atmosphere according to an ordinary method to prepare
Compound (44).
[0370] As the solvent, alcohols such as methanol and ethanol,
ethers such as tetrahydrofuran and 1,4-dioxane, and a solvent
mixture thereof can be used.
[0371] As the palladium catalyst, a catalyst such as palladium
carbon and palladium black can be used.
[0372] The reaction time differs depending on the catalyst, the
solvent, and the like to be used, and is usually 30 minutes to 18
hours, preferably 2 hours to 8 hours. The reaction temperature is
usually 10 to 100.degree. C., preferably 25 to 50.degree. C.
[0373] In the hydrogenation reaction, trialkylsilane such as
triethylsilane can be used as the hydrogen source instead of
hydrogen.
Reaction (ii)
[0374] The reaction of Compound (43) with an alcohol can be carried
out according to a method as described in Chemische Berichte, 1878,
11, 9.
[0375] As the acid, hydrochloric acid, sulfuric acid, and the like
can be used.
[0376] As the alcohol, methanol, ethanol, propanol, butanol, and
the like can be used.
[0377] The reaction time in the reaction of Compound (43) and an
alcohol is usually 2 hours to 24 hours, preferably 5 hours to 20
hours. The reaction temperature is usually 5 to 50.degree. C.,
preferably 25 to 50.degree. C.
[0378] In the reaction with ammonia, a solvent may be used, and as
the solvent, alcohols such as methanol and ethanol, ethers such as
tetrahydrofuran, a solvent mixture thereof, and the like can be
used.
[0379] The reaction time in the reaction with ammonia is usually 3
hours to 24 hours, preferably 8 hours to 20 hours. The reaction
temperature is usually 5 to 50.degree. C., preferably 25 to
50.degree. C.
Reaction (iii)
[0380] The reaction of Compound (43) with lithium
hexamethyldisilazane can be carried out according to a method as
described in J. Organomet. Chem., 1987, 331, 21, 161-167.
[0381] As the solvent, ethers such as tetrahydrofuran, and the like
can be used.
[0382] The reaction time in the reaction with lithium
hexamethyldisilazane is usually 1 hour to 24 hours, preferably 2
hours to 18 hours. The reaction temperature is usually 0 to
50.degree. C., preferably 5 to 30.degree. C.
[0383] As the acid in the treatment with an acid, hydrochloric
acid, hydrobromic acid, and the like can be used.
[0384] In the treatment with an acid, a solvent may be used, and as
the solvent, ethers such as tetrahydrofuran and dioxane and the
like can be used.
[0385] The reaction time in the treatment with an acid differs
depending on the acid, the solvent and the like to be used, and is
usually 30 minutes to 24 hours, preferably 1 hour to 18 hours. The
reaction temperature is usually 0 to 50.degree. C., preferably 5 to
30.degree. C.
Step II:
[0386] Compound (1-B-a) can be prepared by reacting Compound (44)
with Compound (45) and hydrazine in an appropriate solvent in the
presence or absence of a base.
[0387] As the solvent, ethers such as tetrahydrofuran and
1,4-dioxane, halogenated hydrocarbons such as 1,2-dichloroethane
and carbon tetrachloride, alcohols such as methanol and ethanol, a
solvent mixture thereof, and the like can be used.
[0388] As the base, an alkali metal carbonate such as potassium
carbonate and sodium hydrogencarbonate, alkali metal alkoxide such
as sodium methoxide, alkali metal hydroxide such as sodium
hydroxide and potassium hydroxide, and the like can be used.
[0389] Hydrazine used in the present reaction may be in a form of
salt (for example, hydrochloride salt) and/or may be a hydrate.
[0390] The reaction time in the reaction with hydrazine is usually
30 minutes to 12 hours, preferably 30 minutes to 8 hours. The
reaction temperature is usually 25 to 100.degree. C., preferably 50
to 80.degree. C.
[0391] Further, a hydrazide compound (45a) represented by the
formula as below:
##STR00049##
(wherein each symbol has the same meaning as above) may be used
instead of Compound (45) and hydrazine to obtain Compound (1-B-a)
according to a method as described in Tetrahedron Letters, 1987,
28, 5133-5136.
[Method T]
[0392] Compound (1-B) wherein X is --O-- (hereinafter, referred to
as Compound (1-B-b) can be prepared by the process as below:
##STR00050##
(wherein each symbol has the same meaning as above.)
Step I:
[0393] Compound (48) can be prepared by subjecting Compound (46)
and Compound (47) to Mitsunobu reaction (for example, a reaction as
described in Advanced Organic Chemistry PartB (F. A. Carey & R.
J. Sundberg, Springer), Okuda, M.; Tomioka, K.; Tetrahedron Lett
[TELEAY] 1994, 35 (26), 4585-4586, and the like) in an appropriate
solvent in the presence of azodicarboxylates and phosphines.
[0394] As the azodicarboxylates, diethyl azodicarboxylate,
di-t-butyl azodicarboxylate, 1,1'-(azodicarbonyl)dipiperidine, and
the like can be used.
[0395] As the phosphines, triarylphosphines such as
triphenylphosphine, trialkylphosphines such as
tri-n-butylphosphine, and the like can be used.
[0396] As the solvent, ethers such as tetrahydrofuran, 1,4-dioxane
and diethylether, aromatic hydrocarbons such as benzene, toluene
and xylene, halogenated hydrocarbons such as methylene chloride,
1,2-dichloroethane and chloroform, or a solvent mixture thereof can
be used.
[0397] The reaction time differs depending on the reagent, the
solvent, and the like to be used, and is usually 30 minutes to 24
hours, preferably 1 hour to 12 hours. The reaction temperature is
usually 0.degree. C. to 100.degree. C., preferably 25.degree. C. to
80.degree. C.
Step II:
[0398] The deprotection reaction of Compound (48) can be carried
out in a manner similar to Step II of Method R.
[Method U]
[0399] Compound (1-B) wherein X is a single bond and Y.sup.b is
cycloalkyl which may be substituted (hereinafter, referred to as
Compound (1-B-c) can be prepared by the process as below:
##STR00051##
(wherein a group
##STR00052##
represents cycloalkenyl which may be substituted, Y.sup.2
represents cycloalkyl which may be substituted, Lv.sup.10
represents a halogen atom (such as chlorine atom and bromine atom),
or trifluoromethanesulfonyloxy group, Lv.sup.11 represents
B(OH).sub.2 or
##STR00053##
and the other symbols have the same meanings as above.)
Step I:
[0400] Compound (51) can be prepared by a coupling reaction of
Compound (49) with Compound (50), which can be carried out in a
manner similar to Step I of Method R.
Step II:
[0401] Compound (52) can be prepared by subjecting Compound (51) to
a hydrogenation reaction in an appropriate solvent in the presence
of a palladium catalyst under hydrogen atmosphere.
[0402] As the solvent, alcohols such as methanol and ethanol,
ethers such as tetrahydrofuran and 1,4-dioxane, or a solvent
mixture thereof can be used.
[0403] As the palladium catalyst, a catalyst such as palladium
carbon and palladium black can be used.
[0404] The reaction time differs depending on the catalyst, the
solvent, and the like to be used, and is usually 1 hour to 24
hours, preferably 1 hour to 12 hours. The reaction temperature is
usually 20 to 50.degree. C., preferably 20 to 40.degree. C.
Step III:
[0405] The deprotection reaction of Compound (52) can be carried
out in a manner similar to Step II of Method R.
[Method V]
[0406] Compound (1-B) wherein R.sup.2b is alkoxy (hereinafter,
referred to as Compound (1-B-d)) can be prepared by the process as
below:
##STR00054##
(wherein R.sup.2b2 represents alkoxy, and the other symbols have
the same meanings as above.)
[0407] Compound (1-B-d) can be prepared by reacting Compound (53)
with oxalyl chloride or thionyl chloride in an appropriate solvent
in the presence or absence of N, N-dimethyformamide, then reacting
with potassium thiocyanate, and reacting with an alcohol and
hydrazine.
[0408] As the solvent in the reaction with oxalyl chloride or
thionyl chloride, halogenated hydrocarbons such as methylene
chloride, ethers such as tetrahydrofuran, and the like can be
used.
[0409] The reaction time in the reaction with oxalyl chloride or
thionyl chloride is usually 30 minutes to 5 hours, preferably 1
hour to 3 hours. The reaction temperature is usually 0 to
60.degree. C., preferably 20 to 40.degree. C.
[0410] As the solvent in the reaction with potassium thiocyanate,
aromatic hydrocarbons such as toluene, halogenated hydrocarbons
such as methylene chloride, and the like can be used.
[0411] The reaction time in the reaction with potassium thiocyanate
is usually 2 hours to 24 hours, preferably 1 hour to 3 hours. The
reaction temperature is usually 0 to 60.degree. C., preferably 20
to 40.degree. C.
[0412] As the alcohol in the present reaction, methanol, ethanol,
propanol, isopropanol, butanol, t-butanol, and the like can be
used.
[0413] The reaction time in the reaction with alcohol is usually 30
minutes to 5 hours, preferably 1 hour to 3 hours. The reaction
temperature is usually 0 to 100.degree. C., preferably 20 to
40.degree. C.
[0414] The reaction time in the reaction with hydrazine is usually
2 hours to 24 hours, preferably 1 hour to 3 hours. The reaction
temperature is usually 0 to 100.degree. C., preferably 50 to
80.degree. C.
[0415] Hydrazine used in the present reaction may be in a form of
salt (for example, hydrochloride salt), and/or may be in a
hydrate.
[Method W]
[0416] Compound (43) wherein X is --O-- (hereinafter, referred to
as Compound (43a) can be prepared by the process as below:
##STR00055##
(wherein HAL.sub.9 and HAL.sub.10 represent a halogen atom (such as
chlorine atom and bromine atom), and the other symbols have the
same meanings as above.)
Step I:
[0417] The coupling reaction of Compound (54) with Compound (47)
can be carried out in a manner similar to Step I of Method T.
Step II:
[0418] Compound (56) can be prepared by reacting Compound (55) with
a boronic acid ester in an appropriate solvent in the presence of a
palladium catalyst, a ligand and a base.
[0419] As the solvent, ethers such as 1,4-dioxane,
dimethylsulfoxide, aromatic hydrocarbons such as toluene, and the
like can be used.
[0420] As the palladium catalyst, palladium acetate,
[1,1'-bis(diphenylphosphino)ferrocene]palladium (II) dichloride
dichloromethane complex (PdCl.sub.2(dppf)CH.sub.2Cl.sub.2) and the
like can be used.
[0421] As the ligand,
2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (S-PHOS),
2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl
(X-PHOS), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene
(Xantphos), and the like can be used.
[0422] As the base, potassium acetate, potassium phosphate, and the
like can be used.
[0423] As the boronic acid ester, bis(pinacolato)diboron,
trialkoxyboron, and the like can be used.
[0424] The reaction time differs depending on the catalyst, the
solvent, and the like to be used, and is usually 1 hour to 24
hours, preferably 2 hours to 12 hours. The reaction temperature is
usually 50 to 130.degree. C., preferably 60 to 100.degree. C.
Step III: The coupling reaction of Compound (56) with Compound (57)
can be carried out in a manner similar to Step I of Method R.
[Method X]
[0425] Compound (41) wherein R.sup.2b is alkyl which may be
substituted, aromatic hydrocarbon group which may be substituted,
or cycloalkyl which may be substituted (hereinafter, referred to as
Compound (41b)) can be prepared by the process as below:
##STR00056##
(wherein each symbol has the same meaning as above.)
Steps I and II:
[0426] Compound (60) can be prepared in a manner similar to Step I
and Step II of Method S.
Step III:
[0427] Compound (41b) can be prepared by protecting the amino group
of Compound (60). For example, when PG.sub.3 is
2-(trimethylsilyl)ethoxymethyl group, it can be prepared by
reacting Compound (60) with 2-(trimethylsilyl)ethoxymethyl chloride
in an appropriate solvent in the presence of a base.
[0428] As the solvent, an aprotic polar solvent such as
N,N-dimethyformamide, N,N-dimethylacetamide and N-methylpyrrolidone
can be used.
[0429] As the base, an alkali metal hydride such as sodium hydride
and potassium hydride, or an alkali metal carbonate such as
potassium carbonate and sodium carbonate can be used.
[Method Y]
[0430] Compound (41) wherein R.sup.2b is alkylthio (hereinafter,
referred to as Compound (41c)) can be prepared by the process as
below:
##STR00057##
wherein HAL.sub.11 represents a halogen atom such as chlorine atom,
bromine atom and iodine atom), R.sup.2b3 represents alkyl, and the
other symbols have the same meanings as above.
Step I:
[0431] Compound (63) can be prepared by reacting Compound (61) with
Compound (62) in an appropriate solvent in the presence of methyl
iodide, carbon disulfide and a base, and by reacting the obtained
product with hydrazine in an appropriate solvent.
[0432] As the solvent in the reaction of Compound (61) with
Compound (62), amides such as N,N-dimethyformamide, ethers such as
tetrahydrofuran, and the like can be used.
[0433] As the base in the reaction of Compound (61) with Compound
(62), alkyl metal hydride such as sodium hydride and potassium
hydride, and the like can be used.
[0434] The reaction time in the reaction of Compound (61) with
Compound (62) is usually 1 hour to 24 hours, preferably 2 hours to
12 hours. The reaction temperature is usually -10 to 40.degree. C.,
preferably -10 to 25.degree. C.
[0435] As the solvent in the reaction with hydrazine, ethers such
as tetrahydrofuran, alcohols such as methanol and ethanol, a
solvent mixture thereof, and the like can be used.
[0436] Hydrazine used in the present reaction may be in a form of
salt and/or may be a hydrate.
[0437] The reaction time in the reaction with hydrazine is usually
30 minutes to 8 hours, preferably 1 hour to 5 hours. The reaction
temperature is usually 0 to 40.degree. C., preferably 0 to
25.degree. C.
Step II:
[0438] The reaction from Compound (63) to Compound (41c) can be
carried out in a manner similar to Step III of Method X.
[Method Z]
[0439] Compound (63) can also be prepared by the process as
below:
##STR00058##
(wherein each symbol has the same meaning as above.)
Step I:
[0440] Compound (65) can be prepared by reacting Compound (64) with
oxalyl chloride or thionyl chloride in an appropriate solvent in
the presence or absence of N,N-dimethylformamide, followed by
reaction with thiosemicarbazide in an appropriate solvent in the
presence of a base.
[0441] As the solvent in the reaction with oxalyl chloride or
thionyl chloride, halogenated hydrocarbons such as methylene
chloride, ethers such as tetrahydrofuran, and the like can be
used.
[0442] The reaction time in the reaction with oxalyl chloride or
thionyl chloride is usually 30 minutes to 5 hours, preferably 1
hour to 3 hours. The reaction temperature is usually 0 to
60.degree. C., preferably 20 to 40.degree. C.
[0443] As the solvent in the reaction with thiosemicarbazide,
ethers such as tetrahydrofuran, halogenated hydrocarbons such as
methylene chloride, and the like can be used.
[0444] As the base in the reaction with thiosemicarbazide,
pyridine, triethylamine, and the like can be used.
[0445] The reaction time in the reaction with thiosemicarbazide is
usually 2 hours to 24 hours, preferably 1 hour to 3 hours. The
reaction temperature is usually 25 to 100.degree. C., preferably 80
to 100.degree. C.
Step II:
[0446] Compound (63) can be prepared by reacting Compound (65) with
Compound (62) in an appropriate solvent in the presence of an
alkali metal base such as an alkali metal hydroxide and potassium
carbonate.
[0447] As the solvent, a mixed solvent of alcohol such as methanol
and ethanol, and water, and the like can be used.
[0448] As the alkali metal hydroxide base, sodium hydroxide,
potassium hydroxide, and the like can be used.
[0449] The reaction time is usually 30 minutes to 5 hours,
preferably 1 hour to 3 hours. The reaction temperature is usually 0
to 40.degree. C., preferably 0 to 25.degree. C.
[Method AA]
[0450] Compound (41) wherein R.sup.2b is alkoxy which may be
substituted, aryloxy which may be substituted, heteroaryloxy which
may be substituted, cycloalkyloxy, cycloalkylalkoxy, or
non-aromatic heterocycle having a bond at the nitrogen atom which
may be substituted (hereinafter, referred to as Compound (41d)) can
be prepared by the process as below:
##STR00059##
(wherein R.sup.2b4 represents alkoxy which may be substituted,
aryloxy which may be substituted, heteroaryloxy which may be
substituted, cycloalkyloxy, cycloalkylalkoxy, or non-aromatic
heterocycle having a bond at the nitrogen atom which may be
substituted (preferably, piperidino, 1-piperazinyl, morpholino, and
the like), and the other symbols have the same meanings as
above.)
Step I:
[0451] Compound (66) can be prepared by reacting Compound (63a)
with an oxidizing agent in an appropriating solvent.
[0452] As the solvent, halogenated hydrocarbons such as methylene
chloride and chloroform, ethers such as tetrahydrofuran, and the
like can be used.
[0453] As the oxidizing agent, m-chloroperoxybenzoic acid and the
like can be used.
[0454] The reaction time is usually 30 minutes to 24 hours,
preferably 1 hour to 12 hours. The reaction temperature is usually
0 to 40.degree. C., preferably 0 to 25.degree. C.
Step II:
[0455] Compound (41d) can be prepared by reacting Compound (66)
with Compound (67) in an appropriate solvent in the presence of a
base.
[0456] As the solvent, amides such as N, N-dimethyformamide and
N-methylpyrrolidone, ethers such as tetrahydrofuran and
1,4-dioxane, a solvent mixture thereof, and the like can be
used.
[0457] As the base, an alkali metal hydride such as sodium hydride
and potassium hydride, an alkali metal carbonate such as potassium
carbonate and sodium carbonate, an organic bases such as
triethylamine and N,N-diisopropylethylamine, and the like can be
used.
[0458] The reaction time is usually 10 minutes to 24 hours,
preferably 10 minutes to 12 hours. The reaction temperature is
usually 0 to 150.degree. C., preferably 0 to 120.degree. C.
[Method AB]
[0459] Compound (41) wherein R.sup.2b is alkoxy which may be
substituted (hereinafter, referred to as Compound (41e)) can be
prepared by the process as below:
##STR00060##
(wherein R.sup.2b5 represents alkyl which may be substituted, and
the other symbols have the same meanings as above.)
Step I:
[0460] Compound (69) can be prepared by reacting Compound (68) with
a cyanogen halide (such as bromo cyanide) in an appropriate solvent
in the presence of a base, according to a process as described in
Justus Liebigs Annalen der Chemie, 1955, 597, 157-165 and the
like.
[0461] As the solvent, ethers such as 1,4-dioxane, halogenated
hydrocarbons such as methylene chloride, acetonitrile, and the like
can be used.
[0462] As the base, an alkali metal carbonate such as sodium
hydrogencarbonate, an alkali metal hydroxide such as sodium
hydroxide, and the like can be used.
[0463] The reaction time is usually 1 hour to 48 hours, preferably
2 hours to 24 hours. The reaction temperature is usually 0 to
100.degree. C., preferably 25 to 80.degree. C.
Step II:
[0464] Compound (71) can be prepared by reacting Compound (69) with
Compound (70) in the present of an alkali metal hydroxide base.
[0465] As the alkali metal hydroxide base, sodium hydroxide,
potassium hydroxide, and the like can be used.
[0466] The reaction time is usually 1 hour to 24 hours, preferably
3 hours to 12 hours. The reaction temperature is usually 50 to
100.degree. C., preferably 60 to 90.degree. C.
Step III:
[0467] Compound (41e) can be prepared by protecting Compound (71)
in a manner similar to Step III of Method X.
[Method AC]
[0468] Compound (41) wherein R.sup.2b is non-aromatic heterocyclic
group having a bond at the nitrogen atom which may be substituted
(preferably, piperidino, 1-piperazinyl, morpholino, and the like)
(hereinafter, referred to as Compound (410) can be prepared by the
process as below:
##STR00061##
(wherein R.sup.2b6 represents non-aromatic heterocyclic group
having a bond at the nitrogen atom which may be substituted
(preferably, piperidino, 1-piperazinyl, morpholino, and the like),
and the other symbols have the same meanings as above.)
Step I:
[0469] Compound (75) can be prepared by reacting Compound (72),
which can be obtained by reacting benzotriazole with a cyanogen
halide (such as cyanogen bromide), with Compound (73) in an
appropriate solvent in the presence of a base, followed by reaction
with Compound (74) in an appropriate solvent in the presence of a
base.
[0470] As the solvent in the reaction of Compound (72) with
Compound (73), ethers such as tetrahydrofuran and dioxane,
halogenated hydrocarbons such as methylene chloride, acetonitrile,
and the like can be used.
[0471] As the base in the reaction of Compound (72) with Compound
(73), an organic base such as triethylamine, diisopropylethylamine
and pyridine can be used.
[0472] The reaction time in the reaction of Compound (72) with
Compound (73) is usually 1 hour to 24 hours, preferably 3 hours to
12 hours. The reaction temperature is usually 0 to 40.degree. C.,
preferably 0 to 25.degree. C.
[0473] As the solvent in the reaction with Compound (74),
halogenated hydrocarbons such as chloroform and methylene chloride,
ethers such as tetrahydrofuran and dioxane, halogenated
hydrocarbons such as methylene chloride, acetonitrile, and the like
can be used.
[0474] As the base in the reaction with Compound (74), an organic
base such as triethylamine, diisopropylethylamine and pyridine can
be used.
[0475] The reaction time in the reaction with Compound (74) is
usually 1 hour to 24 hours, preferably 1 hour to 12 hours. The
reaction temperature is usually 0 to 60.degree. C., preferably 0 to
40.degree. C.
Step II:
[0476] Compound (76) can be prepared by reacting Compound (75) with
hydrazine in an appropriate solvent according to a method as
described in Synthesis, 2001, 6, 897-903.
[0477] As the solvent, halogenated hydrocarbons such as chloroform
and methylene chloride, and the like can be used.
[0478] The reaction time is usually 1 hour to 24 hours, preferably
3 hour to 12 hours. The reaction temperature is usually 0 to
60.degree. C., preferably 0 to 40.degree. C.
Step III:
[0479] Compound (41f) can be prepared by protecting Compound (76)
in a manner similar to Step III of Method X.
[Method AD]
[0480] Compound (41) wherein R.sup.2b is aromatic hydrocarbon group
which may be substituted (hereinafter, referred to as Compound
(41g)) can be prepared by the process as below:
##STR00062##
(wherein R.sup.2b7 represents aromatic hydrocarbon group which may
be substituted, and the other symbols have the same meanings as
above.)
[0481] Compound (41g) can be prepared by reacting Compound (68)
with Compound (77) in an appropriate solvent in the presence of a
base, and by protecting the amino group with PG.sub.3.
[0482] As the solvent, alcohols such as methanol, ethanol and
isopropylaocohol, and the like can be used.
[0483] As the base, an alkali metal alkoxide such as sodium
methoxide and potassium methoxide, and the like can be used.
[0484] The reaction time is usually 12 hours to 72 hours,
preferably 24 hours to 48 hours. The reaction temperature is
usually 25 to 100.degree. C., preferably 50 to 90.degree. C.
[Method AE]
[0485] Compound (41) wherein R.sup.2b is alkyl which may be
substituted, cycloalkyl which may be substituted, or aromatic
hydrocarbon group which may be substituted (hereinafter, referred
to as Compound (41h)) can be prepared by the process as below:
##STR00063##
(wherein each symbol has the same meaning as above.)
[0486] Compound (79) can be prepared by reacting Compound (58) with
Compound (78) in an appropriate solvent under oxygen atmosphere in
the presence of a base and a catalyst according to a method as
described in J. Am. Chem. Soc. 2009, 131, p. 15080-15081.
[0487] As the solvent, dimethylsulfoxide, N, N-dimethyformamide,
dichlorobenzene, toluene, and the like can be used.
[0488] As the base, an alkali metal carbonate such as sodium
carbonate, potassium carbonate and cesium carbonate, and the like
can be used.
[0489] As the catalyst, a catalyst such as copper (I) chloride,
copper (I) bromide, copper (II) bromide, copper (II) acetate can be
used. Depending on the reactive group, 1,10-phenanthroline and zinc
(II) halide is effective as an additive.
[0490] The reaction time is usually 12 hours to 48 hours,
preferably 12 hours to 24 hours. The reaction temperature is
usually room temperature to the reflux temperature of the solvent,
preferably 80 to 150.degree. C.
Step II:
[0491] A reaction from Compound (79) to Compound (41h) can be
carried out in a manner similar to Step III of Method X.
[Method AF]
[0492] Compound (46) and Compound (49a) which is Compound (49)
wherein LV.sup.10 is trifluoromethanesulfonyloxy can be prepared by
the process as below:
##STR00064##
(wherein PG.sub.4 represents a hydroxyl group-protective group
(preferably, benzyl and the like), and the other symbols have the
same meanings as above.)
Step I:
[0493] The coupling reaction of Compound (41) with Compound (80)
can be carried out in a manner similar to Step I of Method R.
Step II:
[0494] Compound (46) can be prepared by deprotecting PG.sub.4 of
Compound (81).
[0495] The deprotection reaction of PG.sub.4 can be carried, for
example when PG.sub.4 is benzyl group, by subjecting Compound (81)
to a hydrogenation reaction in an appropriate solvent (alcohols
such as methanol and ethanol, and the like) in the presence of
palladium catalyst (such as palladium carbon and palladium
hydroxide) under hydrogen atmosphere to prepare Compound (46).
Step III:
[0496] Compound (49a) can be prepared by reacting Compound (46)
with trifluoromethanesulfonic anhydride in an appropriate solvent
(halogenated hydrocarbons such as methylene chloride and
chloroform, ethers such as tetrahydrofuran and dimethyl ether, and
the like) in the presence of a base (such as triethylamine and
N,N-diisopropylethylamine) at 0.degree. C. to 25.degree. C. for 1
hour to 8 hours.
[0497] The compound represented by the general formula (A) can be
prepared by the above Method A to Method AF, or according to a
method as described in PCT/JP2011/079958.
[0498] When the compound of the present invention, the intermediate
compound, the starting compound, and the like have a functional
group (such as hydroxyl, amino and carboxy), the functional group
can be protected with a protective group which is usually used in
the organic synthetic chemistry and after a reaction, the
protective group can be removed to obtain an intended compound,
according to a method as described in Theodora W. Greene, Peter G.
M. Wuts, "Protective Groups in Organic Synthesis" 3rd. ed., John
Wiley & Sons, Inc., 1999. As the protective group, a protective
group which is usually used in the organic synthetic chemistry
described in the above book can be mentioned, and as a protective
group of hydroxyl group, for example, tetrahydropyranyl,
trimethylsilyl, t-butyldimethylsilyl, benzyl, 4-methoxybenzyl,
methoxymethyl, acetyl, and the like can be mentioned. As a
protective group of amino group, for example, t-butoxycarbonyl,
benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl,
2,2,2-trichloroethoxycarbonyl, t-amyloxycarbonyl, 4-methoxybenzyl,
2-nitrobenzenesulfonyl, 2,4-dinitrobenzenesulfonyl,
2-(trimethylsilyl)ethoxymethyl, and the like can be mentioned, and
as a protective group of carboxy, for example, alkyl such as
methyl, ethyl and t-butyl, benzyl, and the like can be
mentioned.
[0499] Further, after the compound of the present invention or the
intermediate compound is prepared by the above method, the
functional group can be converted or modified according to an
ordinary method. The specific methods can be mentioned as
follows.
(1) Conversion of Carboxy or Ester Thereof to Aminocarbonyl
[0500] By converting a carboxy or a salt thereof to an acyl halide
and reacting it with an amine; by reacting a carboxy or a salt
thereof with an amine in the presence of a condensation agent; or
by reacting an ester thereof with an amine, a carboxy or ester
thereof can be converted to a corresponding aminocarbonyl.
(2) Conversion of Amine to Amide
[0501] By reacting an amine or a salt thereof with a carboxy or a
corresponding acyl halide; by reacting an amine or a salt thereof
with a carboxy in the presence of a condensing agent; or by
reacting an amine with an ester of carboxy, an amine can be
converted to a corresponding amide.
(3) Conversion of Ester to Carboxy
[0502] By hydrolyzing an ester with an alkali metal hydroxide base
(such as sodium hydroxide and potassium hydroxide) or an acid (such
as hydrochloric acid and sulfuric acid); or by hydrogenating using
a metal catalyst, an ester can be converted to a corresponding
carboxy or a salt thereof can be obtained.
(4) Conversion of Ester to Hydroxymethyl
[0503] By reacting an ester with a reducing agent (such as metal
reducing agent including sodium borohydride, lithium borohydride,
lithium aluminium hydride and sodium triacetoxyborohydride), an
ester can be converted to a corresponding hydroxymethyl.
(5) Conversion of Alcohol to Ether
[0504] By reacting an alcohol with an alkyl halide in the presence
of a base, an alcohol can be converted to a corresponding
ether.
(6) Conversion of Alcohol to Aldehyde
[0505] By reacting an alcohol with an oxidizing agent (such as
manganese dioxide), an alcohol can be converted to a corresponding
aldehyde.
(7) Conversion of Aldehyde to Aminomethyl or Cyclic Amiomethyl
[0506] By reacting an aldehyde with an amine or a cyclic amine
(such as piperidine, piperazine and morpholine) in the presence of
a reducing agent (such as metal reducing agent including sodium
borohydride, lithium borohydride, lithium aluminium hydride and
sodium triacetoxyborohydride), an aldehyde can be converted to a
corresponding aminomethyl or cyclic aminomethyl.
(8) Conversion of Halogen to Cyano
[0507] By reacting a halogen with a cyanating agent (such as
potassium hexacyanoferrate (II) trihydrate, copper (I) cyanide and
zinc cyanide) a palladium catalyst (such as palladium acetate and
PdCl.sub.2(dppf)), a ligand (such as butyl di-1-adamantylphosphine,
X-PHOS, S-PHOS and Xantphos), and in the presence or absence of a
base (such as sodium carbonate and potassium carbonate), a halogen
can be converted to a corresponding cyano.
(9) Conversion of Haloalkyl to Carboxy
[0508] By hydrolyzing a haloalkyl with a base (such as an alkali
metal hydroxide base including sodium hydroxide and potassium
hydroxide), a haloalkyl can be converted to a corresponding carboxy
or a salt thereof.
(10) Conversion of Haloalkyl to Cyano
[0509] By treating a haloalkyl with ammonia, a haloalkyl can be
converted to a corresponding cyano or a salt thereof.
(11) Conversion of Alkylthio to Alkylsulfonyl
[0510] By treating an alkylthio with an oxidizing agent (such as
m-chloro-perbenzoic acid), an alkylthio can be converted to a
corresponding alkylsulfonyl.
(12) Conversion of Alkylsulfonyl to Alkoxy, Aryloxy or
Heteroaryloxy
[0511] By reacting an alkylsulfonyl with an alcohol, a hydroxyaryl
or a hydroxyheteroaryl in the presence of a base (such as potassium
carbonate, sodium carbonate and sodium hydride), an alkylsulfonyl
can be converted to a corresponding alkoxy, aryloxy, or
heteroaryloxy.
[0512] Further, the prepared compound of the present invention and
each intermediate compound in the above preparation can be purified
by an ordinary method, for example, chromatography, distillation,
recrystallization, and the like. As the solvent for
recrystallization, for example, an alcohol solvent such as
methanol, ethanol and 2-propanol; an ether solvent such as
diethylether, diisopropylether and THF; an ester solvent such as
ethyl acetate; an aromatic solvent such as toluene; a ketone
solvent such as acetone; a hydrocarbon solvent such as hexane;
water, and the like; or a solvent mixture thereof; and the like can
be mentioned. Further, the compound of the present invention can be
converted to a pharmaceutically acceptable salt thereof according
to an ordinary method, and then, recrystallization and the like can
be carried out.
[0513] If the compound of the present invention or a
pharmaceutically acceptable salt thereof has an optical isomer
based on an asymmetric carbon, they can be separated to each
optical isomer by an ordinary optical resolution method (fractional
crystallization method or separation method using a chiral column)
Further, an optically pure starting compound can be used to
synthesize an optical isomer.
EFFECT OF THE INVENTION
[0514] The compound of the present invention or a pharmaceutically
acceptable salt thereof has an excellent DGAT1 inhibitory activity,
and is useful as a medicament for the prevention and/or treatment
of the following diseases in warm-blooded animals, preferably,
mammals including human being:
(1) diseases relating to adiposity (obesity): hyperlipidemia,
hypertriglyceridemia, lipid metabolism disorder, fatty liver, and
the like, (2) diseases considered to be caused by adiposity
(obesity); type 2 diabetes mellitus, diabetic complication
(including diabetic peripheral neuropathy, diabetic nephropathy,
diabetic retinopathy and diabetic macroangiopathy);
arteriosclerosis, hypertension, cerebrovascular disorder, coronary
artery disease; dyspnoea, lumbago, gonarthrosis, and the like, and
(3) familial hyperchylomicronemia.
[0515] Further, since the compound of the present invention or a
pharmaceutically acceptable salt thereof has GLP-1 secretion
promoting activity based on DGAT1 inhibitory activity, it is
expected to have insulin secretion promoting activity, and/or a
pancreas-protecting activity.
[0516] Thus obtained compound of the present invention or a
pharmaceutically acceptable salt thereof can be formulated as a
pharmaceutically composition comprising a therapeutically effective
amount of the compound and a pharmaceutically acceptable carrier.
As the pharmaceutically acceptable carrier, a binder (for example,
hydroxypropylcellulose, polyvinylalcohol, polyvinylpyrrolidone, or
polyethyleneglycol), excipient (for example, lactose, sucrose,
mannitol, sorbitol, cornstarch, potato starch, crystalline
cellulose or calcium carbonate), a lubricant (for example,
magnesium stearate, calcium stearate or talc), a disintegrating
agent (for example, low substituted hydroxypropylcellulose, or
cross-linked carboxymethylcellulose), a humectant (for example,
sodium lauryl sulfate), and the like can be mentioned.
[0517] The compound of the present invention or a pharmaceutically
acceptable salt thereof can be orally or parenterally administered,
and can be used as an appropriate pharmaceutical preparation. As an
appropriate pharmaceutical preparation for oral administration, for
example, a solid preparation such as tablet, granule, capsule, or
powder; a solution preparation, a suspension preparation, and an
emulsion preparation can be mentioned. As an appropriate
pharmaceutical preparation for parenteral administration,
suppository, injection or drip infusion preparation using distilled
water for injection, physiological saline, glucose aqueous
solution, and the like; inhalant, and the like can be
mentioned.
[0518] The dose of the compound of the present invention or a
pharmaceutically acceptable salt thereof, differs depending on the
administration method; the age, the body weight and the condition
of patient, and it is 0.001 to 100 mg/kg/day, preferably 0.1 to 30
mg/kg/day, more preferably 0.1 to 10 mg/kg/day for usual oral
administration, which is administered in one dose or in 2 to 4
doses. For parenteral administration, 0.0001 to 10 mg/kg/day is
preferable, which is administered in one dose or several doses.
Further, for transmucosal administration, 0.001 to 100 mg/kg/day is
administered once a day or in several doses.
BEST MODE FOR CARRYING OUT THE INVENTION
[0519] The present invention is explained in detail hereinafter
with examples, reference examples and experimental examples, but,
the present invention is not limited thereby.
EXAMPLE
Example 1-1
##STR00065##
[0520] (1) An acetate of Compound 1 (1.94 g) and potassium
carbonate (1.73 g) were dissolved in dichloromethane (50 mL) and
saturated brine (50 mL), to this was added Compound 2 (phenacyl
bromide) (1.49 g), and then the mixture was heated at reflux for 4
hours. After the temperature of the reaction solution was brought
back to room temperature, dichloromethane was added to carry out a
liquid separation. The organic layer was separated and dried over
anhydrous sodium sulfate, and the solvent was distilled off under
reduced pressure. The obtained residue was purified by silica gel
column chromatography (chloroform:methanol=99:1 to 95:5), to the
obtained residue was added diethyl ether, the solid was collected
by filtration, washed with diethyl ether and dried to obtain
Compound 3 (1.93 g).
[0521] MS (m/z): 428 [M+H].sup.+
(2) Compound 3 (0.31 g) was dissolved in methanol (7 mL) and
tetrahydrofuran (7 mL), and an 8N aqueous sodium hydroxide solution
(0.92 mL) was added dropwise, and the mixture was stirred at
50.degree. C. overnight. After the temperature of the reaction
solution was brought back to room temperature, the solvent was
distilled off under reduced pressure, and to the obtained residue
was added water, and the mixture was neutralized with acetic acid.
After the solvent was distilled under reduced pressure, water was
added, and the obtained solid residue was collected by filtration,
washed with water and subsequently dried. To the obtained residue
was added diethyl ether, and the solid was collected by filtration,
washed with diethyl ether and dried to obtain Compound 4 (0.29
g).
[0522] MS (m/z): 414 [M+H].sup.+
Examples 1-2 to 1-69
[0523] A treatment was carried out in a manner similar to the
Example 1-1 to obtain compounds of Examples 1-2 to 1-69 in Table 1
below.
TABLE-US-00001 TABLE 1 Example Starting material 1 Starting
material 2 1-2 ##STR00066## ##STR00067## 1-3 ##STR00068##
##STR00069## 1-4 ##STR00070## ##STR00071## 1-5 ##STR00072##
##STR00073## 1-6 ##STR00074## ##STR00075## 1-7 ##STR00076##
##STR00077## 1-8 ##STR00078## ##STR00079## 1-9 ##STR00080##
##STR00081## 1-10 ##STR00082## ##STR00083## 1-11 ##STR00084##
##STR00085## 1-12 ##STR00086## ##STR00087## 1-13 ##STR00088##
##STR00089## 1-14 ##STR00090## ##STR00091## 1-15 ##STR00092##
##STR00093## 1-16 ##STR00094## ##STR00095## 1-17 ##STR00096##
##STR00097## 1-18 ##STR00098## ##STR00099## 1-19 ##STR00100##
##STR00101## 1-20 ##STR00102## ##STR00103## 1-21 ##STR00104##
##STR00105## 1-22 ##STR00106## ##STR00107## 1-23 ##STR00108##
##STR00109## 1-24 ##STR00110## ##STR00111## 1-25 ##STR00112##
##STR00113## 1-26 ##STR00114## ##STR00115## 1-27 ##STR00116##
##STR00117## 1-28 ##STR00118## ##STR00119## 1-29 ##STR00120##
##STR00121## 1-30 ##STR00122## ##STR00123## 1-31 ##STR00124##
##STR00125## 1-32 ##STR00126## ##STR00127## 1-33 ##STR00128##
##STR00129## 1-34 ##STR00130## ##STR00131## 1-35 ##STR00132##
##STR00133## 1-36 ##STR00134## ##STR00135## 1-37 ##STR00136##
##STR00137## 1-38 ##STR00138## ##STR00139## 1-39 ##STR00140##
##STR00141## 1-40 ##STR00142## ##STR00143## 1-41 ##STR00144##
##STR00145## 1-42 ##STR00146## ##STR00147## 1-43 ##STR00148##
##STR00149## 1-44 ##STR00150## ##STR00151## 1-45 ##STR00152##
##STR00153## 1-46 ##STR00154## ##STR00155## 1-47 ##STR00156##
##STR00157## 1-48 ##STR00158## ##STR00159## 1-49 ##STR00160##
##STR00161## 1-50 ##STR00162## ##STR00163## 1-51 ##STR00164##
##STR00165## 1-52 ##STR00166## ##STR00167## 1-53 ##STR00168##
##STR00169## 1-54 ##STR00170## ##STR00171## 1-55 ##STR00172##
##STR00173## 1-56 ##STR00174## ##STR00175## 1-57 ##STR00176##
##STR00177## 1-58 ##STR00178## ##STR00179## 1-59 ##STR00180##
##STR00181## 1-60 ##STR00182## ##STR00183## 1-61 ##STR00184##
##STR00185## 1-62 ##STR00186## ##STR00187## 1-63 ##STR00188##
##STR00189## 1-64 ##STR00190## ##STR00191## 1-65 ##STR00192##
##STR00193## 1-66 ##STR00194## ##STR00195## 1-67 ##STR00196##
##STR00197## 1-68 ##STR00198## ##STR00199## 1-69 ##STR00200##
##STR00201## Example Product MS (m/z) 1-2 ##STR00202## 432 [M +
H].sup.+ 1-3 ##STR00203## 432 [M + H].sup.+ 1-4 ##STR00204## 432 [M
+ H].sup.+ 1-5 ##STR00205## 450 [M + H].sup.+ 1-6 ##STR00206## 450
[M + H].sup.+ 1-7 ##STR00207## 450 [M + H].sup.+ 1-8 ##STR00208##
450 [M + H].sup.+ 1-9 ##STR00209## 448/450 [M + H].sup.+ 1-10
##STR00210## 448/450 [M + H].sup.+ 1-11 ##STR00211## 482 [M +
H].sup.+ 1-12 ##STR00212## 482 [M + H].sup.+ 1-13 ##STR00213## 482
[M + H].sup.+ 1-14 ##STR00214## 498 [M + H].sup.+ 1-15 ##STR00215##
444 [M + H].sup.+ 1-16 ##STR00216## 444 [M + H].sup.+ 1-17
##STR00217## 488 [M + H].sup.+ 1-18 ##STR00218## 472 [M + H].sup.+
1-19 ##STR00219## 474 [M + H].sup.+ 1-20 ##STR00220## 474 [M +
H].sup.+ 1-21 ##STR00221## 474 [M + H].sup.+ 1-22 ##STR00222## 500
[M + H].sup.+ 1-23 ##STR00223## 512 [M + H].sup.+ 1-24 ##STR00224##
480 [M + H].sup.+ 1-25 ##STR00225## 498 [M + H].sup.+ 1-26
##STR00226## 458 [M + H].sup.+ 1-27 ##STR00227## 415 [M + H].sup.+
1-28 ##STR00228## 429 [M + H].sup.+ 1-29 ##STR00229## 415 [M +
H].sup.+ 1-30 ##STR00230## 415 [M + H].sup.+ 1-31 ##STR00231## 416
[M + H].sup.+ 1-32 ##STR00232## 483 [M + H].sup.+ 1-33 ##STR00233##
483 [M + H].sup.+ 1-34 ##STR00234## 420 [M + H].sup.+ 1-35
##STR00235## 421 [M + H].sup.+ 1-36 ##STR00236## 418 [M + H].sup.+
1-37 ##STR00237## 419 [M + H].sup.+ 1-38 ##STR00238## 414 [M +
H].sup.+ 1-39 ##STR00239## 444 [M + H].sup.+ 1-40 ##STR00240## 498
[M + H].sup.+ 1-41 ##STR00241## 428 [M + H].sup.+ 1-42 ##STR00242##
458 [M + H].sup.+ 1-43 ##STR00243## 512 [M + H].sup.+ 1-44
##STR00244## 428 [M + H].sup.+ 1-45 ##STR00245## 458 [M + H].sup.+
1-46 ##STR00246## 442 [M + H].sup.+ 1-47 ##STR00247## 472 [M +
H].sup.+ 1-48 ##STR00248## 526 [M + H].sup.+ 1-49 ##STR00249## 459
[M + H].sup.+ 1-50 ##STR00250## 429 [M + H].sup.+ 1-51 ##STR00251##
446 [M + H].sup.+ 1-52 ##STR00252## 476 [M + H].sup.+ 1-53
##STR00253## 447 [M + H].sup.+ 1-54 ##STR00254## 416 [M + H].sup.+
1-55 ##STR00255## 444 [M + H].sup.+
1-56 ##STR00256## 428 [M + H].sup.+ 1-57 ##STR00257## 442 [M +
H].sup.+ 1-58 ##STR00258## 458 [M + H].sup.+ 1-59 ##STR00259## 496
[M + H].sup.+ 1-60 ##STR00260## 527 [M + H].sup.+ 1-61 ##STR00261##
427 [M + H].sup.+ 1-62 ##STR00262## 457 [M + H].sup.+ 1-63
##STR00263## 511 [M + H].sup.+ 1-64 ##STR00264## 444 [M + H].sup.+
1-65 ##STR00265## 433 [M + H].sup.+ 1-66 ##STR00266## 432 [M +
H].sup.+ 1-67 ##STR00267## 461 [M + H].sup.+ 1-68 ##STR00268## 461
[M + H].sup.+ 1-69 ##STR00269## 483 [M + H].sup.+
Example 2-1
##STR00270##
[0525] Compound 1 (4.40 g) was suspended in acetonitrile (100 mL),
and a 1N aqueous sodium hydroxide solution (10.6 mL) was added
dropwise, and the mixture was stirred at room temperature
overnight. The obtained solid was collected by filtration, washed
with acetonitrile and subsequently dried to obtain Compound 2 (4.55
g).
[0526] MS (m/z): 412 [M-Na].sup.-
Examples 2-2 to 2-16
[0527] A treatment was carried out in a manner similar to the
Example 2-1 to obtain compounds of Examples 2-2 to 2-16 in Table 2
below.
TABLE-US-00002 TABLE 2 Ex- am- MS ple Starting material Product
(m/z) 2-2 ##STR00271## ##STR00272## 496 [M - Na].sup.- 2-3
##STR00273## ##STR00274## 478/ 480 [M - Na + Cl].sup.- 2-4
##STR00275## ##STR00276## 478 [M - Na].sup.- 2-5 ##STR00277##
##STR00278## 496 [M - Na].sup.- 2-6 ##STR00279## ##STR00280## 456
[M - Na].sup.- 2-7 ##STR00281## ##STR00282## 412 [M - Na].sup.- 2-8
##STR00283## ##STR00284## 442 [M - Na].sup.- 2-9 ##STR00285##
##STR00286## 496 [M - Na].sup.- 2-10 ##STR00287## ##STR00288## 426
[M - Na].sup.- 2-11 ##STR00289## ##STR00290## 456 [M - Na].sup.-
2-12 ##STR00291## ##STR00292## 508/ 510 [M + Cl - Na].sup.- 2-13
##STR00293## ##STR00294## 486 [M - Na].sup.- 2-14 ##STR00295##
##STR00296## 480 [M - Na].sup.- 2-15 ##STR00297## ##STR00298## 508/
510 [M + Cl - Na].sup.- 2-16 ##STR00299## ##STR00300## 442 [M -
Na].sup.-
Example 3-1
##STR00301##
[0528] (1) Compound 1 (300 mg), Compound 2 (163 mg) and potassium
carbonate (308 mg) were added into tetrahydrofuran (8 mL), and
additionally saturated brine (8 mL) was added, and the mixture was
stirred at 80.degree. C. for 3 hours. After the reaction solution
was cooled to room temperature, ethyl acetate and saturated brine
were added to carry out a liquid separation. The organic layer was
separated and subsequently dried over anhydrous sodium sulfate, and
the solvent was distilled off under reduced pressure. To the
obtained residue was added acetic acid (8 mL), and the mixture was
stirred at 80.degree. C. for 2 hours. After the temperature of the
reaction solution was brought back to room temperature, the solvent
was distilled off under reduced pressure, and ethyl acetate and
saturated brine were added to carry out a liquid separation. The
organic layer was separated and subsequently dried over anhydrous
sodium sulfate, and the solvent was distilled off under reduced
pressure. The obtained residue was purified by silica gel column
chromatography (chloroform:methanol=100:0 to 97:3) to obtain
Compound 3 (144 mg).
[0529] MS (m/z) 444 [M+H].sup.+
(2) Compound 3 (142 mg) was treated in a manner similar to the
Example 1-1 (2) to obtain Compound 4 (115 mg).
[0530] MS (m/z): 430 [M+H].sup.+
Examples 3-2 to 3-13
[0531] A treatment was carried out in a manner similar to the
Example 3-1 to obtain compounds of Examples 3-2 to 3-13 in Table 3
below.
TABLE-US-00003 TABLE 3 Example Starting material 1 Starting
material 2 3-2 ##STR00302## ##STR00303## 3-3 ##STR00304##
##STR00305## 3-4 ##STR00306## ##STR00307## 3-5 ##STR00308##
##STR00309## 3-6 ##STR00310## ##STR00311## 3-7 ##STR00312##
##STR00313## 3-8 ##STR00314## ##STR00315## 3-9 ##STR00316##
##STR00317## 3-10 ##STR00318## ##STR00319## 3-11 ##STR00320##
##STR00321## 3-12 ##STR00322## ##STR00323## 3-13 ##STR00324##
##STR00325## Example Product MS (m/z) 3-2 ##STR00326## 514 [M +
H].sup.+ 3-3 ##STR00327## 446 [M + H].sup.+ 3-4 ##STR00328## 500 [M
+ H].sup.+ 3-5 ##STR00329## 445 [M + H].sup.+ 3-6 ##STR00330## 475
[M + H].sup.+ 3-7 ##STR00331## 529 [M + H].sup.+ 3-8 ##STR00332##
414 [M + H].sup.+ 3-9 ##STR00333## 444 [M + H].sup.+ 3-10
##STR00334## 498 [M + H].sup.+ 3-11 ##STR00335## 428 [M + H].sup.+
3-12 ##STR00336## 458 [M + H].sup.+ 3-13 ##STR00337## 512 [M +
H].sup.+
Example 4-1
##STR00338##
[0532] (1) Compound 1 (250 mg) and Compound 2 (105 mg) were treated
in a manner similar to the Example 1-1 (1) to obtain Compound 3
(131.9 mg).
[0533] MS (m/z): 503 [M+H].sup.+
(2) Compound 3 (130 mg) was dissolved in trifluoroacetic acid (3
mL) and water (0.3 mL), and the mixture was stirred at room
temperature for 3 hours. The residue obtained by concentration
under reduced pressure was dissolved in tetrahydrofuran, and the
mixture was neutralized with a 1N aqueous sodium hydroxide
solution. After a few drops of acetic acid was added, ethyl acetate
and water were added to carry out a liquid separation. The organic
layer was separated and subsequently dried over anhydrous sodium
sulfate, and the solvent was distilled off under reduced pressure.
To the obtained residue were added diethyl ether, diisopropyl ether
and ethyl acetate, the mixture was powderized and the solvent was
distilled off under reduced pressure. To the obtained residue was
added diisopropyl ether, and the powder was collected by filtration
and dried to obtain Compound 4 (94.5 mg).
[0534] MS (m/z) 447 [M+H].sup.+
Examples 4-2 to 4-16
[0535] A treatment was carried out in a manner similar to the
Example 4-1 to obtain compounds of Examples 4-2 to 4-16 in Table 4
below.
TABLE-US-00004 TABLE 4 Example Starting material 1 Starting
material 2 4-2 ##STR00339## ##STR00340## 4-3 ##STR00341##
##STR00342## 4-4 ##STR00343## ##STR00344## 4-5 ##STR00345##
##STR00346## 4-6 ##STR00347## ##STR00348## 4-7 ##STR00349##
##STR00350## 4-8 ##STR00351## ##STR00352## 4-9 ##STR00353##
##STR00354## 4-10 ##STR00355## ##STR00356## 4-11 ##STR00357##
##STR00358## 4-12 ##STR00359## ##STR00360## 4-13 ##STR00361##
##STR00362## 4-14 ##STR00363## ##STR00364## 4-15 ##STR00365##
##STR00366## 4-16 ##STR00367## ##STR00368## MS Example Product
(m/z) 4-2 ##STR00369## 477 [M + H].sup.+ 4-3 ##STR00370## 442 [M +
H].sup.+ 4-4 ##STR00371## 472 [M + H].sup.+ 4-5 ##STR00372## 526 [M
+ H].sup.+ 4-6 ##STR00373## 459 [M + H].sup.+ 4-7 ##STR00374## 489
[M + H].sup.+ 4-8 ##STR00375## 458 [M + H].sup.+ 4-9 ##STR00376##
488 [M + H].sup.+ 4-10 ##STR00377## 441 [M + H].sup.+ 4-11
##STR00378## 471 [M + H].sup.+ 4-12 ##STR00379## 428 [M + H].sup.+
4-13 ##STR00380## 458 [M + H].sup.+ 4-14 ##STR00381## 512 [M +
H].sup.+ 4-15 ##STR00382## 444 [M + H].sup.+ 4-16 ##STR00383## 474
[M + H].sup.+
Example 5-1
##STR00384##
[0537] Compound 1 (300 mg), Compound 2 (187 mg) and potassium
carbonate (308 mg) were added to tetrahydrofuran (8 mL), and
additionally saturated brine (8 mL) was added, and the mixture was
stirred at 80.degree. C. for 5 hours. After the reaction solution
was cooled to room temperature, ethyl acetate and saturated brine
were added to carry out a liquid separation. The organic layer was
separated and dried over anhydrous sodium sulfate, and subsequently
the solvent was distilled off under reduced pressure. The obtained
residue was purified by silica gel column chromatography
(chloroform:methanol=100:0 to 94:6). The obtained solid was
dissolved in methanol (5 mL) and tetrahydrofuran (5 mL), and a 2N
aqueous sodium hydroxide solution (1.52 mL) was added, and the
mixture was stirred at 50.degree. C. for 3 hours. To the residue
obtained by concentration under reduced pressure were added water
and acetic acid, and the deposited solid was washed with water and
dried to obtain Compound 3 (117.2 mg).
[0538] MS (m/z) 460 [M+H].sup.+
Example 5-2
[0539] A treatment was carried out in a manner similar to the
Example 5-1 to obtain a compound of Example 5-2 in Table 5
below.
TABLE-US-00005 TABLE 5 Example Starting material 1 Starting
material 2 5-2 ##STR00385## ##STR00386## MS Example Product (m/z)
5-2 ##STR00387## 498 [M + H].sup.+
Example 6
##STR00388## ##STR00389## ##STR00390##
[0540] (1) Compound 1 (696 mg) and Compound 2 (665 mg) were treated
in a manner similar to Example 1-1 (1) to obtain Compound 3 (938
mg).
[0541] MS (m/z): 562 [M+H].sup.+
(2) Compound 3 (936 mg) was dissolved in N,N-dimethylformamide (9
mL), and 60% sodium hydride (87 mg) was added under a nitrogen
atmosphere under ice cooling, and the mixture was stirred. After 1
hour, 2-(trimethylsilyl)ethoxymethyl chloride (442 .mu.L) was added
under ice cooling, and the mixture was stirred overnight while the
temperature gradually brought back to room temperature. To the
reaction solution was added a saturated aqueous ammonium chloride
solution, and a liquid separation was carried out between ethyl
acetate and water. The organic layer was dried over anhydrous
sodium sulfate and subsequently the solvent was distilled off under
reduced pressure. The obtained residue was purified by silica gel
column chromatography (n-hexane:ethyl acetate=85:15 to 65:35) to
obtain Compound 4 (782 mg).
[0542] MS (m/z): 692 [M+H].sup.+
(3) Compound 4 (782 mg) was dissolved in methanol (15 mL) and
tetrahydrofuran (15 mL), 10% palladium carbon (300 mg) was added
under a nitrogen atmosphere and subsequently a hydrogen atmosphere
was substituted therefor, and the mixture was stirred at room
temperature for 3 hours. The insoluble substance was filtered
through a membrane-filter and the filtrate was concentrated under
reduced pressure to obtain Compound 5 (658 mg).
[0543] MS (m/z): 602 [M+H].sup.+
(4) Compound 5 (655 mg) was dissolved in tetrahydrofuran (13 mL)
and triethylamine (182 .mu.L) and isobutyl chloroformate (169
.mu.L) were added under ice cooling, and the mixture was stirred
for 30 minutes. The obtained solid was filtered and washed with
tetrahydrofuran, and subsequently to the filtrate was added sodium
borohydride (62 mg) under ice cooling, and the mixture was stirred
for two days while the temperature brought back to room
temperature. To the reaction solution was added a saturated aqueous
ammonium chloride solution and a liquid separation was carried out
between ethyl acetate and water. The organic layer was separated
and dried over anhydrous sodium sulfate, and subsequently the
solvent was distilled off under reduced pressure. The obtained
residue was purified by silica gel column chromatography
(chloroform:methanol=100:0 to 95:5) to obtain Compound 6 (553
mg).
[0544] MS (m/z): 588 [M+H].sup.+
(5) Compound 6 (551 mg) was dissolved in dichloromethane (11 mL)
and manganese dioxide (815 mg) was added, and the mixture was
stirred at room temperature overnight.
[0545] The insoluble substance was filtered through a
membrane-filter, and the filtrate was concentrated under reduced
pressure to obtain Compound 7 (443 mg).
[0546] MS (m/z): 586 [M+H].sup.+
(6) Compound 7 (441 mg) was dissolved in tetrahydrofuran (9 mL) and
morpholine (132 .mu.L) was added, and the mixture was stirred.
After 1 hour, sodium triacetoxyborohydride (479 mg) and acetic acid
(43 .mu.L) were added, and the mixture was further stirred at room
temperature overnight. Dichloromethane and a saturated aqueous
sodium hydrogen carbonate solution were added to the reaction
solution to carry out a liquid separation. The organic layer was
washed with water, and dried over anhydrous sodium sulfate. The
solvent was distilled off under reduced pressure. The obtained
residue was purified by silica gel column chromatography
(n-hexane:ethyl acetate=50:50 to 0:100) to obtain Compound 8 (477
mg).
[0547] MS (m/z): 657 [M+H].sup.+
(7) Compound 8 (475 mg) was dissolved in trifluoroacetic acid (10
mL) and water (1 mL), and the mixture was stirred at room
temperature overnight. After the solvent was distilled off under
reduced pressure, ethyl acetate and a saturated aqueous sodium
hydrogen carbonate solution were added to the residue to carry out
a liquid separation. The organic layer was washed with water, and
dried over anhydrous sodium sulfate. The solvent was distilled off
under reduced pressure. The obtained residue was dissolved in
methanol (5 mL) and tetrahydrofuran (5 mL) and a 2N aqueous sodium
hydroxide solution (1.8 mL) was added under ice cooling, and the
mixture was stirred at room temperature overnight. To the reaction
solution was added 2N hydrochloric acid (1.8 mL), and the solvent
was distilled off under reduced pressure. The obtained residue was
purified by preparative LC-MS to obtain Compound 9 (264 mg).
[0548] MS (m/z): 513 [M+H].sup.+
Example 7
##STR00391## ##STR00392## ##STR00393##
[0549] (1) Compound 1 (1000 mg), Compound 2 (986 mg) and a
[1,1'-bis(diphenylphosphino)ferrocene]palladium
dichloride-dichloromethane complex (193 mg) were dissolved in
N,N-dimethylformamide (12 mL), and a 2M aqueous sodium carbonate
solution (3.55 mL) was added, and the mixture was stirred under a
nitrogen atmosphere at 65.degree. C. for 6 hours. After the
reaction solution was cooled to room temperature, brine and ethyl
acetate were added to carry out a liquid separation. After the
organic layer was separated, anhydrous magnesium sulfate and
activated charcoal were added and filtered through Celite. The
filtrate was concentrated under reduce pressure. The obtained
residue was purified by silica gel column chromatography
(n-hexane:ethyl acetate=88:12, 80:20 and to 75:25) to obtain
Compound 3 (1.14 g).
[0550] MS (m/z): 550 [M+H].sup.+
(2) Compound 3 (2.56 g) was dissolved in trifluoroacetic acid (40
mL) and water (6 mL), and the mixture was stirred at room
temperature overnight. To the residue obtained by concentration
under reduce pressure was added a saturated aqueous sodium hydrogen
carbonate solution, and the mixture was extracted with ethyl
acetate and tetrahydrofuran. The organic layer was washed with
saturated brine and subsequently dried over anhydrous sodium
sulfate, and the solvent was distilled off under reduced pressure.
The obtained residue was purified by silica gel column
chromatography (chloroform:methanol=100:0 to 95:5) to obtain
Compound 4 (1.90 g).
[0551] MS (m/z): 420 [M+H].sup.+
(3) Compound 4 (1.88 g) was dissolved in methanol (20 mL) and
tetrahydrofuran (20 mL), and 28% aqueous ammonia (40 mL) was added,
and the mixture was stirred at 40.degree. C. overnight. Further,
28% aqueous ammonia (10 mL) was added in two parts, and the mixture
was stirred at 40.degree. C. overnight. After the temperature of
the reaction solution brought back to room temperature, the solvent
was distilled off under reduced pressure, and ethyl acetate,
tetrahydrofuran and water were added to the obtained residue to
carry out a liquid separation. The organic layer was washed with
saturated brine and subsequently dried over anhydrous magnesium
sulfate, and the solvent was distilled off under reduced pressure.
The obtained residue was purified with silica gel column
chromatography (chloroform:methanol=100:0 to 96:4) to obtain
Compound 5 (1.16 g).
[0552] MS (m/z): 377 [M+H].sup.+
(4) A treatment was carried out in a manner similar to Example 6
(2) using Compound 5 (854 mg) to obtain Compound 6 (1.09 g).
[0553] MS (m/z): 507 [M+H].sup.+
(5) A treatment was carried out in a manner similar to Reference
Example 7-1 (4) using Compound 6 (1.08 g) to obtain Compound 7
(1.14 g).
[0554] MS (m/z): 540 [M+H].sup.+
(6) To Compound 7 (1.14 g) was added acetic anhydride (15 mL), and
the mixture was stirred at 120.degree. C. for 2 hours. After the
temperature of the reaction solution brought back to room
temperature, the solvent was distilled off under reduced pressure
(including an azeotropic procedure using toluene (three times)), to
the obtained residue added a saturated aqueous sodium hydrogen
carbonate solution, and the mixture was extracted with ethyl
acetate. The organic layer was washed with saturated brine, and the
aqueous layer thus obtained was further extracted with ethyl
acetate. After the organic layers were combined and dried over
anhydrous sodium sulfate, the solvent was distilled off under
reduced pressure. The obtained residue was purified by silica gel
column chromatography (n-hexane:ethyl acetate) to obtain Compound 8
(679 mg).
[0555] MS (m/z): 564 [M+H].sup.+
(7) A treatment was carried out in a manner similar to the Example
6 (7) using Compound 8 (672 mg) to obtain Compound 9 (389 mg).
[0556] MS (m/z): 420 [M+H].sup.+
Example 8
##STR00394##
[0557] (1) Compound 1 (102 mg) and Compound 2 (119 mg) were
dissolved in dimethylformamide (2.5 mL), and a palladium chloride
(dppf)-methylene chloride complex (10 mg) and a 2M aqueous sodium
carbonate solution (0.5 mL) were added, and the mixture was stirred
under a nitrogen atmosphere at 70.degree. C. for 8 hours. Water and
ethyl acetate were added to the reaction mixture to carry out a
liquid separation, to the organic layer was added hexane, and the
solution was washed with water and saturated brine. After the
organic layer was dried over anhydrous sodium sulfate, the solvent
was distilled off under reduced pressure, and the obtained residue
was purified by silica gel column chromatography (hexane:ethyl
acetate=90:10 to 67:33) to obtain Compound 3 (81 mg).
[0558] MS (m/z): 582 [M+H].sup.+
(2) A treatment was carried out in a manner similar to the Example
7 (2) using Compound 3 (80 mg) to obtain Compound 4 (51 mg)
[0559] MS (m/z): 452 [M+H].sup.+
(3) A treatment was carried out in a manner similar to the Example
1-1 (2) using Compound 4 (43 mg) to obtain Compound 5 (36 mg).
[0560] MS (m/z): 438 [M+H].sup.+
Example 9
##STR00395##
[0561] (1) Compound 1 (9.43 g), Compound 2 (10 g) and sodium
carbonate (8.77 g) were added to a mixed solvent of toluene (285
mL), ethanol (143 mL) and water (143 mL), and the atmosphere was
replaced with a nitrogen atmosphere. To this was added
tetrakistriphenylphosphine palladium (0.48 g), and the mixture was
heated at reflux for 16 hours. After the reaction solution was
cooled to room temperature, ethyl acetate and water were added to
carry out a liquid separation. The organic layer was separated and
dried over anhydrous magnesium sulfate, and subsequently the
solvent was distilled off under reduced pressure. The obtained
solid was crystallized from ethyl acetate to obtain Compound 3
(10.55 g).
[0562] MS (m/z): 340/342 [M+H].sup.+
(2) Compound 3 (1000 mg), bis(pinacolato)diborane (933 mg) and
potassium acetate (865 mg) were added to 1,4-dioxane (29 mL), and
the mixture was subjected to nitrogen substitution. To this were
added a palladium chloride (dppf)-methylene chloride complex (72
mg) and dppf (49 mg) and then nitrogen substitution was carried
out, and the mixture was stirred at 80.degree. C. overnight. To the
reaction solution were added water and ethyl acetate, and the
mixture was stirred, and filtered through Celite. The organic layer
was separated, and anhydrous magnesium sulfate and activated
charcoal were added, and the mixture was filtered through Celite.
The solvent was distilled off under reduced pressure. To the
obtained residue was added methanol, and the solid was collected by
filtration to obtain Compound 4 (803 mg).
[0563] MS (m/z): 388 [M+H].sup.+
##STR00396##
(3) A treatment was carried out in a manner similar to the Example
6 (2) using Compound 5 (10 g) to obtain a mixture of Compound 6 and
Compound 7 (13.27 g).
[0564] MS (m/z): 423/425 [M+H].sup.+
##STR00397##
(4) Compound 4 (800 mg) and the mixture of Compound 6 and Compound
7 (1139 mg) were added to a mixed solvent of a 2M aqueous sodium
carbonate solution (4131 .mu.L) and dimethoxyethane (17 mL), and
the mixture was subjected to nitrogen substitution. To this was
added tetrakis(triphenylphosphine)palladium (24 mg), and the
mixture was stirred at 80.degree. C. for 12 hours. To the reaction
solution were added ethyl acetate and water, and the mixture was
stirred. The insoluble substance was filtered out. The organic
layer was separated, washed with saturated brine, and dried over
anhydrous magnesium sulfate. The solvent was distilled off under
reduced pressure. The obtained residue was purified by silica gel
column chromatography (n-hexane:ethyl acetate=91:9 to 67:33) to
obtain a mixture of Compound 8 and Compound 9 (749 mg).
[0565] MS (m/z): 604/606 [M+H].sup.+
(5) A mixture of Compound 8 and Compound 9 (500 mg), phenylboronic
acid (151 mg) and a 2M aqueous sodium carbonate solution (1654
.mu.L) were added to a mixed solvent of dimethoxyethane (5 mL) and
ethanol (5 mL), and the mixture was subjected to nitrogen
substitution. To this was added a palladium chloride
(dppf)-methylene chloride complex (68 mg), and the mixture was
stirred at 80.degree. C. overnight. Ethyl acetate and water were
added to the reaction solution to carry out a liquid separation.
The organic layer was separated and washed with saturated brine,
and dried over anhydrous magnesium sulfate. The solvent was
distilled off under reduced pressure. The obtained residue was
purified by silica gel column chromatography (n-hexane:ethyl
acetate=90:10 to 85:15) to obtain a mixture of Compound 10 and
Compound 11 (403 mg).
[0566] MS (m/z): 602 [M+H].sup.+
(6) The mixture of Compound 10 and Compound 11 (400 mg) was
dissolved in methanol (8 mL), and palladium-carbon (80 mg) was
added, and the mixture was stirred under a hydrogen atmosphere at
room temperature for 5 hours. The insoluble matter was filtered
through a membrane-filter, and the filtrate was concentrated under
reduced pressure to obtain a mixture of Compound 12 and Compound 13
(300 mg).
[0567] MS (m/z): 512 [M+H].sup.+
##STR00398## ##STR00399##
(7) A treatment was carried out in a manner similar to Reference
Example 7-1 (1) using the mixture of Compound 12 and Compound 13
(300 mg) to obtain a mixture of Compound 14 and Compound 15 (58
mg).
[0568] MS (m/z): 626 [M+H].sup.+
(8) A treatment was carried out in a manner similar to the Example
1-1 (2) using the mixture of Compound 14 and Compound 15 (58 mg) to
obtain a mixture of Compound 16 and Compound 17 (57 mg).
[0569] MS (m/z): 612 [M+H].sup.+
(9) A treatment was carried out in a manner similar to the Example
7 (2) using the mixture of Compound 16 and Compound 17 (57 mg) to
obtain Compound 18 (34 mg).
[0570] MS (m/z): 482 [M+H].sup.+
Example 10
##STR00400## ##STR00401## ##STR00402##
[0571] (1) A treatment was carried out in a manner similar to the
Example 7 (1) using Compound 1 (6.69 g) and Compound 2 (6.04 g) to
obtain Compound 3 (6.54 g).
[0572] MS (m/z): 622 [M+H].sup.+
(2) Compound 3 (1.14 g) was dissolved in tetrahydrofuran (30 mL),
and lithium aluminum hydride (104 mg) was added under ice cooling,
and the mixture was stirred at 0.degree. C. for 20 minutes. To the
reaction solution were added sequentially water (1 mL), a 15%
aqueous sodium hydroxide solution (1 mL) and water (2 mL), and the
mixture was stirred under ice cooling for 30 minutes. The reaction
solution was filtered through Celite, and the filtrate was
concentrated under reduced pressure. The obtained residue was
dissolved in tetrahydrofuran, the pH was adjusted to below 4 with a
10% aqueous citric acid solution, and ethyl acetate was added to
carry out a liquid separation. The organic layer was separated and
washed with water and saturated brine, and dried over anhydrous
sodium sulfate. The solvent was distilled off under reduced
pressure. The obtained residue was purified by silica gel column
chromatography (chloroform:methanol=100:0 to 85:15), to the
obtained solid were added ice-cold ethyl acetate and n-hexane, and
the solid was collected by filtration to obtain Compound 4 (872
mg).
[0573] MS (m/z): 518 [M+H].sup.+
(3) Compound 4 (290 mg) was dissolved in tetrahydrofuran (10 mL)
and N,N-dimethylformamide (10 mL), and 60% sodium hydride (34 mg)
was added, and the mixture was sonicated for 1 minute. To this was
added benzyl bromide (125 mg) at room temperature, and the mixture
was further stirred at room temperature for 6 hours. Diethyl ether,
n-hexane, ethyl acetate and water were added to the reaction
solution to carry out a liquid separation. The organic layer was
separated and washed with water and saturated brine, and dried over
anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure. To the obtained residue were added diisopropyl
ether and n-hexane, and the solid was collected by filtration to
obtain Compound 5 (293 mg).
[0574] MS (m/z): 608 [M+H].sup.+
(4) Compound 5 (290 mg) was dissolved in methylene chloride (8 mL),
and trifluoroacetic acid (4 mL) was added under ice cooling, and
the mixture was stirred for 1 hour under the same conditions. To
the reaction mixture was added an aqueous saturated sodium
bicarbonate solution to make it basic (>pH 8), and a liquid
separation was carried out by addition of ethyl acetate. The
organic layer was separated and washed with water and saturated
brine, and dried over anhydrous sodium sulfate. The solvent was
distilled off under reduced pressure. The obtained residue was
purified by silica gel column chromatography
(chloroform:methanol=100:0 to 90:10), to the obtained residue were
added diisopropyl ether and n-hexane, and the solid was collected
by filtration to obtain Compound 6 (209 mg).
[0575] MS (m/z): 488 [M+H].sup.+
(5) A treatment was carried out in a manner similar to Reference
Example 7-1 (1) using Compound 6 (208 mg) and Compound 7 (113 mg)
to obtain Compound 8 (127 mg).
[0576] MS (m/z): 602 [M+H].sup.+
(6) A treatment was carried out in a manner similar to Example 7
(2) using Compound 8 (127 mg) to obtain Compound 9 (67 mg).
[0577] MS (m/z): 472 [M+H].sup.+
(7) A treatment was carried out in a manner similar to Example 1-1
(2) using Compound 9 (67 mg) to obtain Compound 10 (34 mg).
[0578] MS (m/z): 458 [M+H].sup.+
Example 11
##STR00403## ##STR00404##
[0579] (1) Compound 1 (2.46 g) was dissolved in a mixed solvent of
N,N-dimethylformamide (10 mL) and tetrahydrofuran (20 mL), and 60%
sodium hydride (276 mg) was added under ice cooling. After the
reaction solution was stirred for 5 minutes, to this solution was
added benzyl bromide (1.18 g), and the solution was further stirred
under ice cooling for 2 hours. To the reaction solution was added a
10% aqueous citric acid solution to adjust the pH to 4, and diethyl
ether was added to carry out a liquid separation. The organic layer
was separated and washed with water and saturated brine, and dried
over anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure. The obtained residue was purified by silica gel
column chromatography (chloroform:ethyl acetate=100:0 to 85:15) to
obtain Compound 2 (2.82 g).
[0580] MS (m/z): 518 [M+H].sup.+
(2) A treatment was carried out in a manner similar to the Example
1-1 (2) using Compound 2 (2.82 g) to obtain Compound 3 (2.58
g).
[0581] MS (m/z): 504 [M+H].sup.+
(3) Compound 3 (200 mg), Compound 4 (83 mg), 1-hydroxybenzotriazole
(107 mg), and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide
hydrochloride (152 mg) were added to N,N-dimethylformamide, and the
mixture was stirred at room temperature for two days. The solvent
was distilled off under reduced pressure, and ethyl acetate and a
saturated aqueous sodium hydrogen carbonate solution were added to
the obtained residue to carry out a liquid separation. The organic
layer was separated, and washed with a 10% aqueous citric acid
solution, water and saturated brine, and dried over anhydrous
sodium sulfate. The solvent was distilled off under reduced
pressure. The obtained residue was purified by silica gel column
chromatography (chloroform:methanol=100:0 to 85:15) to obtain
Compound 5 (119 mg).
[0582] MS (m/z): 591 [M+H].sup.+
(4) Compound 5 (115 mg) was dissolved in tetrahydrofuran (10 mL),
and 20% palladium hydroxide-carbon (130 mg) was added, and the
mixture was stirred under a hydrogen atmosphere at room temperature
for 8 hours. The solvent was substituted with ethanol (10 mL), and
the mixture was stirred under a hydrogen atmosphere at 75.degree.
C. for 4 hours. The reaction solution was subject to nitrogen gas
substitution, subsequently diluted with chloroform and methanol,
and filtered. The solvent was distilled off under reduced pressure,
the obtained residue was purified by silica gel column
chromatography (chloroform:methanol=100:0 to 85:15), the obtained
oil was solidified with diethyl ether and diisopropyl ether, and
the obtained solid was collected by filtration to obtain Compound 6
(36 mg).
[0583] MS (m/z): 501 [M+H].sup.+
Example 12
##STR00405##
[0584] (1) Compound 1 (see Compound 3 in Example 1-1) (200 mg) and
N-chlorosuccinimide (102 mg) were added to chloroform (30 mL), and
the mixture was stirred at room temperature overnight. Additional
N-chlorosuccinimide (102 mg) was added, and the mixture was further
stirred for 4 hours. The reaction solution was purified by silica
gel column chromatography (chloroform:ethyl acetate=100:0 to
50:50), and the obtained oil was solidified with diisopropyl ether,
and dilutied with n-hexane. Subsequently, the solid was collected
by filtration to obtain Compound 2 (207 mg).
[0585] MS (m/z): 462/464 [M+H].sup.+
(2) Compound 2 (100 mg), methanol (500 .mu.L), and 60% sodium
hydride (26 mg) were added to 1,4-dioxane (5 mL), and the mixture
was stirred at 95.degree. C. for 1 hour. N,N-Dimethylacetamide (5
mL) was added, and the mixture was stirred at 95.degree. C.
overnight. A 10% aqueous citric acid solution, n-hexane and ethyl
acetate were added to the reaction mixture to carry out a liquid
separation. The organic layer was separated, washed with water and
saturated brine, dried over sodium sulfate and concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (chloroform:ethyl acetate=100:0 to 50:50), and to
the obtained solid were added diisopropyl ether and isopropyl
alcohol, and filtered to obtain Compound 3 (51 mg).
[0586] MS (m/z): 448/450 [M+H].sup.+
Example 13
##STR00406##
[0587] (1) Compound 1 (250 mg), acetamidine hydrochloride (70 mg),
copper bromide (4 mg), and cesium carbonate (482 mg) were added to
dimethylsulfoxide (4 mL), and the mixture was stirred at
120.degree. C. overnight. To the reaction solution were added water
and ethyl acetate, and the mixture was stirred. The insoluble
substance was filtered. The organic layer of the filtrate was
separated, washed with saturated brine, and dried over anhydrous
sodium sulfate. The solvent was distilled off under reduced
pressure. The obtained residue was purified by silica gel column
chromatography (chloroform:methanol=100:0 to 90:10), LC-MS
preparative, and diol silica gel column chromatography
(n-hexane:ethyl acetate=50:50 to 0:100) to obtain Compound 2 (20.4
mg).
[0588] MS (m/z): 563 [M+H].sup.+
(2) A treatment was carried out in a manner similar to the Example
6 (7) using Compound 2 (19 mg) to obtain Compound 3 (11.5 mg).
[0589] MS (m/z): 419 [M+H].sup.+
Example 14
##STR00407##
[0590] (1) A treatment was carried out in a manner similar to
Example 6 (2) using Compound 1 (120 mg) to obtain Compound 2 (112
mg).
[0591] MS (m/z): 636/638 [M+H].sup.+
(2) Compound 2 (110 mg), K.sub.4[Fe(CN).sub.6]3H.sub.2O (37 mg),
palladium acetate (4 mg), butyl di-1-adamantylphosphine (19 mg) and
sodium carbonate (4 mg) were added to N-methylpyrrolidone (2 mL),
and the mixture was stirred under a nitrogen atmosphere at
140.degree. C. for 2.5 hours and then at 160.degree. C. for 3
hours. After the reaction solution was cooled to room temperature,
ethyl acetate and water were added thereto to carry out a liquid
separation. The organic layer was separated, washed with water and
saturated brine, and dried over magnesium sulfate. The solvent was
distilled off under reduced pressure. The obtained residue was
purified by silica gel column chromatography (n-hexane:ethyl
acetate=90:10 to 50:50) to obtain Compound 3 (32 mg).
[0592] MS (m/z): 627 [M+H].sup.+
(3) To Compound 3 (30 mg) was added a 1M tetrabutylammonium
fluoride-tetrahydrofuran solution (239 .mu.L), and the mixture was
stirred at room temperature for 2.5 hours and further 60.degree. C.
for 4 hours. A saturated aqueous sodium hydrogen carbonate solution
and ethyl acetate were added to the reaction solution to carry out
a liquid separation. The organic layer was separated, washed with
saturated brine, and dried over anhydrous magnesium sulfate. The
solvent was distilled off under reduced pressure. The obtained
residue was dissolved in methanol (1 mL) a 1N aqueous sodium
hydroxide solution (479 .mu.L) was added, and the mixture was
stirred at room temperature for 17 hours. After 1N hydrochloric
acid (479 .mu.L) was added to the reaction solution, ethyl acetate
was added to carry out a liquid separation. The organic layer was
separated, washed with saturated brine, and dried over anhydrous
magnesium sulfate. The solvent was distilled off under reduced
pressure. After the obtained residue was purified by silica gel
column chromatography (n-hexane:ethyl acetate=100:0 to 90:10),
diethyl ether was added. The solid was collected by filtration and
dried to obtain Compound 4 (13.8 mg).
[0593] MS (m/z): 483 [M+H].sup.+
Example 15-1
##STR00408##
[0594] (1) Compound 1 (1394 mg) was dissolved in methanol (14 mL),
and sodium methylate (35 mg) was added, and the mixture was stirred
at room temperature overnight. To the reaction solution was added
ammonium chloride (377 mg), and the mixture was stirred at room
temperature for 1 hour and then heated at reflux for 7 hours. The
reaction solution was concentrated under reduced pressure, to the
obtained residue was added ethyl acetate, and the solid was
collected by filtration and dried to obtain Compound 2 (1268 mg) as
a hydrochloride salt.
[0595] MS (m/z): 234/236 [M+H].sup.+
(2) A treatment was carried out in a manner similar to the Example
3-1 (1) using Compound 2 (600 mg) and Compound 3 (533 mg) to obtain
Compound 4 (465 mg).
[0596] MS (m/z): 364/366 [M+H].sup.+
(3) A treatment was carried out in a manner similar to Example 6
(2) using Compound 4 (450 mg) to obtain Compound 5 (605 mg).
[0597] MS (m/z): 494/496 [M+H].sup.+
(4) A treatment was carried out in a manner similar to Example 7
(1) using Compound 5 (300 mg) and Compound 6 (253 mg) to obtain
Compound 7 (88 mg).
[0598] MS (m/z): 634/635 [M+H].sup.+
(5) A treatment was carried out in a manner similar to Example 6
(7) using Compound 7 (85 mg) to obtain Compound 8 (59 mg).
[0599] MS (m/z): 491/493 [M+H].sup.+
Example 15-2
[0600] A treatment was carried out in a manner similar to the
Example 15-1 to obtain a compound of Example 15-2 in Table 6
below.
TABLE-US-00006 TABLE 6 Exam- MS ple Starting material Bromoketone
Product (m/z) 15-2 ##STR00409## ##STR00410## ##STR00411## 461/463
[M + H].sup.+
Example 16
##STR00412##
[0602] Compound 1 (see Reference Example 7-11) (200 mg), Compound 2
(175 mg) and potassium carbonate (242 mg) were added to a mixed
solvent of chloroform (5 mL) and saturated brine (5 mL), and the
mixture was stirred at 70.degree. C. for 7 hours. The organic layer
was separated from the reaction solution and dried over anhydrous
sodium sulfate, and subsequently the solvent was distilled off
under reduced pressure. The obtained residue was dissolved in
methanol (7 mL) and tetrahydrofuran (7 mL), a 2N aqueous sodium
hydroxide solution (2186 .mu.L) was added, and the mixture was
stirred at 50.degree. C. for 5 hours. The reaction solution was
concentrated under reduced pressure, and to the obtained residue
was added trifluoroacetic acid (5 mL), and the mixture was stirred
at room temperature for 7 hours. The reaction solution was
concentrated under reduced pressure, and to the obtained residue
was added a small amount of tetrahydrofuran, and neutralized with a
1N aqueous sodium hydroxide solution. After a few drops of acetic
acid was added to the reaction solution, ethyl acetate was added
thereto to carry out a liquid separation. The organic layer was
separated and dried over anhydrous sodium sulfate, and subsequently
the solvent was distilled off under reduced pressure. The obtained
residue was purified by silica gel column chromatography
(chloroform:methanol=100:0 to 94:6), solidified from diethyl ether
and collected by filtration to obtain Compound 3 (12.3 mg).
[0603] MS (m/z): 510 [M+H].sup.+
Example 17
##STR00413##
[0604] (1) A treatment was carried out in a manner similar to the
Example 7 (1) using a mixture of Compound 1 and Compound 2 (300 mg)
and Compound 3 (357 mg) to obtain a mixture of Compound 4 and
Compound 5 (317 mg).
[0605] MS (m/z): 574 [M+H].sup.+
(2) A treatment was carried out in a manner similar to the Example
7 (2) using the mixture of Compound 4 and Compound 5(369 mg) to
obtain Compound 6 (235 mg).
[0606] MS (m/z): 444 [M+H].sup.+
(3) A treatment was carried out in a manner similar to the Example
1-1 (2) using Compound 6 (195 mg) to obtain Compound 7 (160
mg).
[0607] MS (m/z): 430 [M+H].sup.+
Example 18-1
##STR00414##
[0608] (1) A treatment was carried out in a manner similar to the
Example 7 (1) using Compound 1 (1.0 g) and Compound 2 (1.08 g) to
obtain Compound 3 (1.04 g).
[0609] MS (m/z): 525 [M+H].sup.+
(2) Compound 3 (770 mg) was dissolved in methanol (8 mL) and
tetrahydrofuran (6 mL), 10% palladium-carbon (154 mg) was added
under a nitrogen atmosphere, a hydrogen atmosphere was substituted
therefor, and the mixture was stirred at room temperature for 5
hours. The reaction mixture was filtered through a membrane-filter,
and the filtrate was concentrated under reduced pressure. The
obtained residue was diluted with methanol, to this was added
activated charcoal, the mixture was filtered through Celite, and
the filtrate was concentrated under reduced pressure. The residue
was crystallized by sonication to obtain Compound 4 (612 mg).
[0610] MS (m/z): 436 [M+H].sup.+
(3) Compound 4 (150 mg), Compound 5 (119 mg) and
1,1'-(azodicarbinyl)dipiperidine (ADDP) (217 mg) were mixed in
tetrahydrofuran (3 mL), to this was added tributylphosphine (213
.mu.L), and the mixture was stirred at 70.degree. C. for 8 hours.
Compound 5 (119 mg), 1,1'-(azodicarbinyl)dipiperidine (217 mg) and
tributylphosphine (213 .mu.L) were additionally added, and the
mixture was stirred at 70.degree. C. for further 2.5 hours. To the
reaction solution was added diethyl ether, and the insoluble matter
was filtered. The filtrate was concentrated under reduced pressure,
and purificated by silica gel column chromatography (n-hexane:ethyl
acetate=85:15 to 67:33) to obtain Compound 6 (117 mg).
[0611] MS (m/z): 590 [M+H].sup.+
(4) A treatment was carried out in a manner similar to the Example
7 (2) using Compound 6 (117 mg) to obtain Compound 7 (74 mg).
[0612] MS (m/z): 460 [M+H].sup.+
(5) A treatment was carried out in a manner similar to the Example
1-1 (2) using Compound 7 (73 mg) to obtain Compound 8 (27.5
mg).
[0613] MS (m/z): 446 [M+H].sup.+
Example 18-2
[0614] A treatment was carried out in a manner similar to the
Example 18-1 to obtain a compound of Example 18-2 in Table 7
below.
TABLE-US-00007 TABLE 7 Example Intermediate 1 Intermediate 2 18-2
##STR00415## ##STR00416## MS Example Product (m/z) 18-2
##STR00417## 446 [M + H].sup.+
Example 19-1
##STR00418##
[0615] (1) A treatment was carried out in a manner similar to the
Example 18-1 (3) using Compound 1 (100 mg) and Compound 2 (168 mg)
to obtain Compound 3 (152 mg).
[0616] MS (m/z): 662 [M+H].sup.+
(2) Compound 3 (151 mg) was dissolved in trifluoroacetic acid (3
mL) and water (0.3 mL), and the mixture was stirred at room
temperature overnight. The reaction solution was concentrated under
reduced pressure, the obtained residue was dissolved in
tetrahydrofuran, and 0.1N phosphate buffer (pH 7) and ethyl acetate
were added to be mixed. The organic layer was separated and
concentrated under reduced pressure. To the obtained residue was
added cooled methanol, and the solid was collected by filtration to
obtain Compound 4 (89.7 mg).
[0617] MS (m/z): 476 [M+H].sup.+
Examples 19-2 to 19-4
[0618] A treatment was carried out in a manner similar to the
Example 19-1 to obtain compounds of Examples 19-2 to 19-4 in Table
8 below.
TABLE-US-00008 TABLE 8 Example Intermediate 1 Intermediate 2 19-2
##STR00419## ##STR00420## 19-3 ##STR00421## ##STR00422## 19-4
##STR00423## ##STR00424## MS Example Product (m/z) 19-2
##STR00425## 476 [M + H].sup.+ 19-3 ##STR00426## 490 [M + H].sup.+
19-4 ##STR00427## 477 [M + H].sup.+
Example 20-1
##STR00428##
[0619] (1) A treatment was carried out in a manner similar to the
Example 18-1 (3) using Compound 1 (200 mg) and Compound 2 (323 mg)
to obtain Compound 3 (232 mg).
[0620] MS (m/z): 652 [M+H].sup.+
(2) Compound 3 (230 mg) was dissolved in trifluoroacetic acid (2.3
mL) and water (0.2 mL), and the mixture was stood at room
temperature for one day. The reaction solution was concentrated
under reduced pressure, and ethyl acetate and a saturated aqueous
sodium hydrogen carbonate solution were added to carry out a liquid
separation. The organic layer was separated, washed with saturated
brine, and dried over anhydrous magnesium sulfate. The solvent was
distilled off under reduced pressure. The obtained residue was
dissolved in methanol (4.6 mL) and tetrahydrofuran (2.3 mL), 10%
palladium-carbon (46 mg) was added, and the mixture was stirred
under a hydrogen atmosphere for 7 hours. The reaction solution was
filtered, the filtrate was concentrated under reduced pressure, and
the obtained solid was collected by filtration and dried to obtain
Compound 4 (145 mg).
[0621] MS (m/z): 432 [M+H].sup.+
Example 20-2
[0622] A treatment was carried out in a manner similar to the
Example 20-1 to obtain a compound of Example 20-2 in Table 9
below.
TABLE-US-00009 TABLE 9 Example Intermediate 1 Intermediate 2 20-2
##STR00429## ##STR00430## MS Example Product (m/z) 20-2
##STR00431## 432 [M + H].sup.+
Example 21-1
##STR00432##
[0623] (1) A treatment was carried out in a manner similar to the
Example 18-1 (3) using Compound 1 (300 mg) and Compound 2 (343 mg)
to obtain Compound 3 (438 mg).
[0624] MS (m/z): 666 [M+H].sup.+
(2) A treatment was carried out in a manner similar to the Example
18-1 (2) using Compound 3 (438 mg) to obtain Compound 4 (260
mg).
[0625] MS (m/z): 576 [M+H].sup.+
(3) A treatment was carried out in a manner similar to the Example
7 (2) using Compound 4 (260 mg) to obtain Compound 5 (185 mg) as a
racemate.
[0626] MS (m/z): 446 [M+H].sup.+
Examples 21-2 to 21-4
[0627] A treatment was carried out in a manner similar to the
Example 21-1 to obtain compounds of Examples 21-2 to 21-4 in Table
10 below.
TABLE-US-00010 TABLE 10 Example Intermediate 1 Intermediate 2 21-2
##STR00433## ##STR00434## 21-3 ##STR00435## ##STR00436## 21-4
##STR00437## ##STR00438## MS Example Product (m/z) 21-2
##STR00439## 446 [M + H].sup.+ 21-3 ##STR00440## 446 [M + H].sup.+
21-4 ##STR00441## 446 [M + H].sup.+
Example 22
##STR00442##
[0628] (1) A treatment was carried out in a manner similar to the
Example 18-1 (3) using Compound 1 (1.55 g) and 4-bromophenol (1.62
g) to obtain Compound 2 (0.408 g).
[0629] MS (m/z): 420/422 [M+NH.sub.4].sup.+
(2) Compound 2 (400 mg), tris(dibenzylideneacetone)dipalladium(0)
(18 mg),
2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl
(X-PHOS) (19 mg), potassium acetate (292 mg) and bis pinacolato
diboron (504 mg) were added to 1,4-dioxane (20 mL), and the mixture
was heated at reflux under a nitrogen atmosphere overnight. The
reaction solution was cooled to room temperature and subsequently
filtered through Celite, and the filtrate was concentrated under
reduced pressure. The obtained residue was purified by silica gel
column chromatography (n-hexane:ethyl acetate=99:1 to 93:7) to
obtain Compound 3 (461 mg).
[0630] MS (m/z): 468 [M+NH4].sup.+
(3) A treatment was carried out in a manner similar to the Example
7 (1) using Compound 3 (460 mg) and Compound 4 (287 mg) to obtain
Compound 5 (521 mg).
[0631] MS (m/z): 666 [M+H].sup.+
(4) A treatment was carried out in a manner similar to the Example
18-1 (2) and Example 7 (2) using Compound 5 (520 mg) to obtain
Compound 6 (203 mg).
[0632] MS (m/z): 446 [M+H].sup.+
Example 23-1
##STR00443## ##STR00444##
[0633] (1) A treatment was carried out in a manner similar to the
Example 7 (1) using a mixture of Compound 1 and Compound 2 (1.14
g); and Compound 3 (0.8 g) to obtain a mixture of Compound 4 and
Compound 5 (749 mg).
[0634] MS (m/z): 604/606 [M+H].sup.+
(2) A mixture of Compound 4 and Compound 5 (748 mg), methylboronic
acid (148 mg) and cesium carbonate (806 mg) were added to
1,4-dioxane (15 mL). Under a nitrogen atmosphere, a palladium
chloride (dppf)-methylene chloride complex (101 mg) was added, and
the mixture was stirred at 80.degree. C. overnight. The reaction
solution was cooled to room temperature, subsequently treated with
NH-silica gel, and eluted with ethyl acetate. The eluate was
concentrated, the obtained residue, methylboronic acid (148 mg) and
cesium carbonate (806 mg) were added to 1,4-dioxane (15 mL). Under
a nitrogen atmosphere, a palladium chloride (dppf)-methylene
chloride complex (101 mg) was added, and the mixture was stirred at
80.degree. C. for 2.5 hours. The reaction solution was cooled to
room temperature, subsequently treated with NH-silica gel, and
eluted with ethyl acetate. The eluate was concentrated, and the
obtained residue was purified by silica gel column chromatography
(n-hexane:ethyl acetate=90:10 to 70:30) to obtain a mixture of
Compound 6 and Compound 7 (579 mg).
[0635] MS (m/z): 540 [M+H].sup.+
(3) A treatment was carried out in a manner similar to the Example
18-1 (2) using the mixture of Compound 6 and Compound 7 (579 mg) to
obtain a mixture of Compound 8 and Compound 9 (476 mg).
[0636] MS (m/z): 450 [M+H].sup.+
##STR00445##
(4) A treatment was carried out in a manner similar to the Example
18-1 (3) using the mixture of Compound 8 and Compound 9 (161 mg);
and Compound 10 (231 mg) to obtain a mixture of Compound 11 and
Compound 12 (131 mg).
[0637] MS (m/z): 676 [M+H].sup.+
(5) A treatment was carried out in a manner similar to the Example
19-1 (2) using the mixture of Compound 11 and Compound 12 (109 mg)
to obtain Compound 13 (39.9 mg).
[0638] MS (m/z): 490 [M+H].sup.+
Example 23-2
[0639] A treatment was carried out in a manner similar to the
Example 23-1 to obtain a compound of Example 23-2 in Table 11
below.
TABLE-US-00011 TABLE 11 Example Intermediate 1 Intermediate 2 23-2
##STR00446## ##STR00447## MS Example Product (m/z) 23-2
##STR00448## 420 [M + H].sup.+
Example 24-1
##STR00449##
[0640] (1) A treatment was carried out in a manner similar to the
Example 1-1 (1) using Compound 1 (100 mg) and Compound 2 (64 mg) to
obtain Compound 3 (96 mg).
[0641] MS (m/z): 436 [M+H].sup.+
(2) A treatment was carried out in a manner similar to the Example
1-1 (2) using Compound 3 (128 mg) to obtain Compound 4 (102
mg).
[0642] MS (m/z): 422 [M+H].sup.+
Example 24-2
[0643] A treatment was carried out in a manner similar to the
Example 24-1 to obtain a compound of Example 24-2 in Table 12
below.
TABLE-US-00012 TABLE 12 Example Intermediate 1 Intermediate 2 24-2
##STR00450## ##STR00451## MS Example Product (m/z) 24-2
##STR00452## 438 [M + H].sup.+
Example 25
##STR00453## ##STR00454##
[0644] (1) A treatment was carried out in a manner similar to the
Example 11 (1) using Compound 1 (1.0 g) to obtain Compound 2 (2.68
g).
[0645] MS (m/z): 382/384 [M+H].sup.+
(2) A treatment was carried out in a manner similar to the Example
7 (1) and the Example 1-1 (2) using Compound 2 (1.28 g) and
Compound 3 (2.24 g) to obtain Compound 4 (1.51 g).
[0646] MS (m/z): 496 [M+H].sup.+
(3) A treatment was carried out in a manner similar to the Example
11 (3) using Compound 4 (600 mg) and Compound 5 (351 mg) to obtain
Compound 6 (531 mg).
[0647] MS (m/z): 623 [M+H].sup.+
(4) A treatment was carried out in a manner similar to the Example
11 (4) using Compound 6 (530 mg) to obtain Compound 7 (161 mg).
[0648] MS (m/z): 533 [M+H].sup.+
(5) Compound 7 (140 mg) was dissolved in acetic acid (2 mL) and
water (400 .mu.L), and the mixture was stirred at room temperature
for 6 hours. Water, ethyl acetate and tetrahydrofuran were added to
the reaction solution to carry out a liquid separation. The organic
layer was separated, washed with water, a saturated aqueous sodium
hydrogen carbonate solution and saturated brine, and dried over
anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure. After the obtained residue was purified by
thin-layer silica gel chromatography (chloroform:methanol=5:1), the
residue were solidified with addition of t-butyl alcohol and
n-hexane, and subsequently the solid was collected by filtration to
obtain Compound 8 (38 mg).
[0649] MS (m/z): 493 [M+H].sup.+
Example 26-1
##STR00455##
[0651] A treatment was carried out in a manner similar to the
Example 11 (3) using Compound 1 (300 mg) and Compound 2 (99 mg) to
obtain Compound 3 (161 mg).
[0652] MS (m/z): 477 [M+H].sup.+
Example 26-2
[0653] A treatment was carried out in a manner similar to the
Example 26-1 to obtain a compound of Example 26-2 in Table 13
below.
TABLE-US-00013 TABLE 13 MS Example Starting material 1 Product
(m/z) 26-2 ##STR00456## ##STR00457## 463 [M + H].sup.+
Example 27
##STR00458##
[0655] Compound 1 (60 mg), triethylamine (176 .mu.L), ammonium
chloride (68 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (EDC.HCl) (173 mg) and 1-hydroxybenzotriazole (HOBt)
(51 mg) were added to dimethylsulfoxide (1 mL), and the mixture was
stirred at room temperature overnight. Ethyl acetate and water were
added to the reaction solution to carry out a liquid separation.
The organic layer was separated, washed with water, and dried over
anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure. The obtained residue was purified by thin layer
silica gel column chromatography (chloroform:methanol=99:1) to
obtain Compound 2 (51 mg).
[0656] MS (m/z): 475 [M+H].sup.+
Example 28
##STR00459##
[0657] (1) A treatment was carried out in a manner similar to
Example 31-1 (3) using Compound 1 (300 mg) and ethyl iodide (70
.mu.L) to obtain Compound 2 (270 mg).
[0658] MS (m/z): 546 [M+H].sup.+
(2) A treatment was carried out in a manner similar to the Example
10-(4) using Compound 2 (268 mg) to obtain Compound 3 (180 mg).
[0659] MS (m/z): 426 [M+H].sup.+
(3) A treatment was carried out in a manner similar to Reference
Example 7-1 (1) and the Example 7 (2) using Compound 3 (179 mg) to
obtain Compound 4 (20 mg).
[0660] MS (m/z): 410 [M+H].sup.+
(4) A treatment was carried out in a manner similar to the Example
1-1 (2) using Compound 4 (19 mg) to obtain Compound 5 (10 mg).
[0661] MS (m/z): 396 [M+H].sup.+
Example 29-1
##STR00460##
[0662] (1) Compound 1 (see Example 24-2) (50 mg) and
N-chlorosuccinimide (16.3 mg) were added to N,N-dimethylformamide
(0.6 mL), and the mixture was stirred at room temperature
overnight. The separately prepared Compound 1 (250 mg) and
N-chlorosuccinimide (81.3 mg) were added to N,N-dimethylformamide
(3.1 mL), and the mixture was stirred at room temperature
overnight. The above reaction solutions are combined, and ethyl
acetate and an aqueous saturated sodium hydrogen carbonate solution
were added to carry out a liquid separation. The organic layer was
separated and washed with saturated brine and water, and
subsequently the solvent was distilled off under reduced pressure.
The obtained residue was purified by silica gel column
chromatography (n-hexane:ethyl acetate=80:20 to 67:33) to obtain
Compound 2 (236 mg).
[0663] MS (m/z): 486/488 [M+H].sup.+
(2) A treatment was carried out in a manner similar to the Example
1-1 (2) using Compound 2 (235 mg) to obtain Compound 3 (237
mg).
[0664] MS (m/z): 472/474 [M+H].sup.+
Examples 29-2 to 29-3
[0665] A treatment was carried out in a manner similar to the
Example 29-1 to obtain compounds of Examples 29-2 and 29-3 in Table
14 below.
TABLE-US-00014 TABLE 14 Example Intermediate 29-2 ##STR00461## 29-3
##STR00462## MS Example Product (m/z) 29-2 ##STR00463## 397/399 [M
+ H].sup.+ 29-3 ##STR00464## 406/408/410 [M + H].sup.+
Example 30
##STR00465## ##STR00466##
[0666] (1) A treatment was carried out in a manner similar to the
Example 7 (1) using Compound 1 (2.0 g) and Compound 2 (2.42 g) to
obtain Compound 3 (2.00 g).
[0667] MS (m/z): 516/518 [M+H].sup.+
(2) A treatment was carried out in a manner similar to the Example
7 (2) using Compound 3 (950 mg) to obtain Compound 4 (665 mg).
[0668] MS (m/z): 386/388 [M+H].sup.+
(3) Compound 4 (50 mg), N,N-dimethylformamide diethyl acetal (33
.mu.L) and triethylamine (1.8 .mu.L) were added to toluene (1 mL),
and the mixture was stirred at 110.degree. C. overnight. After the
reaction solution was cooled to room temperature, 1N hydrochloric
acid (1.3 mL) was added, and the mixture was stirred for 30
minutes. A 1N aqueous sodium hydroxide solution (1.3 mL) and ethyl
acetate were added to the reaction solution to carry out a liquid
separation. The organic layer was separated and washed with 0.1N
phosphate buffer (pH 7), and subsequently the solvent was distilled
off under reduced pressure. The obtained residue was purified by
silica gel column chromatography (n-hexane:ethyl acetate=80:20 to
70:30) to obtain Compound 5 (34 mg).
[0669] MS (m/z): 414/416 [M+H].sup.+
(4) Compound 5 (34 mg) was mixed with sodium borohydride (31.1 mg)
in methanol (1.4 mL), to this was added tetrahydrofuran (2 mL), and
the mixture was stirred at 65.degree. C. for 1 minute and then at
room temperature for 15 minutes. The reaction solution was
concentrated under reduced pressure, and ethyl acetate and water
were added to the residue to carry out a liquid separation. The
organic layer was separated, and the solvent was distilled off
under reduced pressure. To the obtained solid was added
acetonitrile, and the solid was collected by filtration and dried
to obtain Compound 6 (30.5 mg).
[0670] MS (m/z): 416/418 [M+H].sup.+ [0671] (5) A treatment was
carried out in a manner similar to the Example 1-1 (2) using
Compound 6 (30.5 mg) to obtain Compound 7 (20 mg).
[0672] MS (m/z): 402/404 [M+H].sup.+
Example 31-1
##STR00467##
[0673] (1) A treatment was carried out in a manner similar to the
Example 6 (2) using Compound 1 (409 mg) to obtain Compound 2 (411
mg).
[0674] MS (m/z): 544/546 [M+H].sup.+
(2) A treatment was carried out in a manner similar to the Example
30 (4) using Compound 2 (408 mg) to obtain Compound 3 (357 mg).
[0675] MS (m/z): 546/548 [M+H].sup.+
(3) Compound 3 (177 mg) was dissolved in N,N-dimethylformamide (1.8
mL) and tetrahydrofuran (1.8 mL), 60% sodium hydride (19.4 mg) was
added under ice cooling, and the mixture was stirred for 5 minutes.
Methyl iodide (40 .mu.L) was added, and the mixture was stirred
under ice cooling for 10 minutes and then at room temperature for 2
hours. Water, a saturated aqueous sodium hydrogen carbonate
solution and ethyl acetate were added to the reaction solution to
carry out a liquid separation. The organic layer was separated and
washed with brine, and subsequently the solvent was distilled off
under reduced pressure. The obtained solid was dissolved in
methanol (1.8 mL) and tetrahydrofuran (1.8 mL), a 2N aqueous sodium
hydroxide solution (1.29 mL) was added, and the mixture was stirred
at room temperature overnight. After acetic acid was added to the
reaction solution, then brine and ethyl acetate were added to carry
out a liquid separation. The organic layer was separated and washed
with 0.1N phosphate buffer (pH 7), and subsequently the solvent was
distilled off under reduced pressure to obtain Compound 4 (199
mg).
[0676] MS (m/z): 546/548 [M+H].sup.+
(4) A treatment was carried out in a manner similar to the Example
7 (2) using Compound 4 (199 mg) to obtain Compound 5 (63 mg).
[0677] MS (m/z): 416/418 [M+H].sup.+
Example 31-2
[0678] A treatment was carried out in a manner similar to the
Example 31-1 to obtain a compound of Example 31-2 in Table 15
below.
TABLE-US-00015 TABLE 15 Alkylating Example Intermediate agent 31-2
##STR00468## Et--I MS Example Product (m/z) 31-2 ##STR00469##
430/432 [M + H].sup.+
Example 32-1
##STR00470##
[0680] Compound 1 (see PCT/JP2011/079958) (470 mg) was dissolved in
28% aqueous ammonia (20 mL), and the mixture was stirred at room
temperature for 4 days and at 40.degree. C. overnight. After the
reaction solution was concentrated under reduced pressure, the
obtained residue was purified by silica gel column chromatography
(chloroform:methanol=100:0 to 85:15), subsequently to the obtained
solid were added isopropyl alcohol and diisopropyl ether, and the
solid was collected by filtration to obtain Compound 2 (300
mg).
[0681] MS (m/z): 363 [M+H].sup.+
Examples 32-2 to 32-4
[0682] A treatment was carried out in a manner similar to the
Example 32-1 to obtain compounds of Examples 32-2 to 32-4 in Table
16 below.
TABLE-US-00016 TABLE 16 Example Intermediate 32-2 ##STR00471## 32-3
##STR00472## 32-4 ##STR00473## MS Example Product (m/z) 32-2
##STR00474## 377 [M + H].sup.+ 32-3 ##STR00475## 378 [M + H].sup.+
32-4 ##STR00476## 364 [M + H].sup.+
Example 33
##STR00477##
[0683] (1) A treatment was carried out in a manner similar to the
Example 11 (3) using Compound 1 (570 mg) and a 2M dimethyl
amine-tetrahydrofuran solution (3.2 mL) to obtain Compound 2 (139
mg).
[0684] MS (m/z): 295/297 [M+H].sup.+
(2) A treatment was carried out in a manner similar to the Example
6 (2) using Compound 2 (260 mg) to obtain Compound 3 (292 mg).
[0685] MS (m/z): 425/427 [M+H].sup.+
(3) A treatment was carried out in a manner similar to the Example
7 (1) using Compound 3 (292 mg) and Compound 4 (344 mg) to obtain
Compound 5 (350 mg).
[0686] MS (m/z): 577 [M+H].sup.+
(4) A treatment was carried out in a manner similar to the Example
6 (7) using
[0687] Compound 5 (350 mg) to obtain Compound 6 (178 mg).
[0688] MS (m/z): 433 [M+H].sup.+
Example 34
##STR00478## ##STR00479##
[0689] (1) A treatment was carried out in a manner similar to the
Example 7 (1) using Compound 1 (see Reference Example 15-1) (1.5 g)
and Compound 2 (1.4 g) to obtain Compound 3 (1.35 g).
[0690] MS (m/z): 592 [M+H].sup.+
(2) A treatment was carried out in a manner similar to the Example
18-1 (2) using Compound 3 (1.30 g) to obtain Compound 4 (860
mg).
[0691] MS (m/z): 412 [M+H].sup.+
(3) Compound 4 (480 mg), N,N-diisopropylethylamine (408 .mu.L) and
ethyl iodide (187 .mu.L) were added to N,N-dimethylacetamide (5
mL), and the mixture was stirred at room temperature for 4 hours.
To the reaction mixture was added water, the supernatant was
discarded, the obtained oily deposit was washed with water and
n-hexane, and subsequently ethyl acetate and a 10% aqueous citric
acid solution were added to carry out a liquid separation. The
organic layer was separated, washed with water and saturated brine,
and dried over magnesium sulfate. The solvent was distilled off
under reduced pressure. The obtained residue was purified by silica
gel column chromatography (ethyl acetate:chloroform=0:100 to 40:60)
to obtain Compound 5 (359 mg).
[0692] MS (m/z): 440 [M+H].sup.+
(4) A treatment was carried out in a manner similar to Reference
Example 7-1 (1) and the Example 7 (2) using Compound 5 (359 mg) and
Compound 6 (340 mg) to obtain Compound 7 (228 mg).
[0693] MS (m/z): 500 [M+H].sup.+
(5) A treatment was carried out in a manner similar to the Example
18-1 (2) using Compound 7 (225 mg) to obtain Compound 8 (165
mg).
[0694] MS (m/z): 410 [M+H].sup.+
Example 35-1
##STR00480##
[0695] (1) Compound 1 (80 mg), Compound 2 (26 mg),
1-hydroxybenzotriazole (25 mg), and
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (36 mg)
were added to N,N-dimethylformamide (1 mL), and the mixture was
stirred at room temperature overnight. The solvent was distilled
off under reduced pressure, and the obtained residue was purified
by thin layer silica gel chromatography (chloroform:methanol) to
obtain Compound 3 (40 mg).
[0696] MS (m/z): 450/452 [M+H].sup.+
(2) Compound 3 (40 mg) was dissolved in a mixed solvent of ethanol
and dichloromethane, and a 4N hydrochloric acid-1,4-dioxane
solution (23 .mu.L) was added. The reaction solution was
concentrated under reduced pressure, and to the obtained solid
residue was added diethyl ether, and the mixture was triturated,
filtered and dried to obtain Compound 4 (42.8 mg) as a
hydrochloride salt.
[0697] MS (m/z): 450/452 [M+H].sup.+
Example 35-2
[0698] A treatment was carried out in a manner similar to the
Example 35-1 to obtain a compound of Example 35-2 in Table 17
below.
TABLE-US-00017 TABLE 17 Example Intermediate 1 Intermediate 2 35-2
##STR00481## ##STR00482## MS Example Product (m/z) 35-2
##STR00483## 431 [M + H].sup.+
Example 36
##STR00484##
[0699] (1) Compound 1 (414 mg), Compound 2 (500 mg), copper (I)
iodide (16 mg), N,N'-dimethylethylenediamine (19 .mu.L) and
potassium phosphate (868 mg) were added to toluene (2.3 mL), and
the mixture was stirred at 80.degree. C. overnight. The reaction
solution was cooled and subsequently filtered through Celite, and
the filtrate was concentrated under reduced pressure. The obtained
residue was purified by silica gel column chromatography
(n-hexane:ethyl acetate=67:33 to 38:62) to obtain Compound 3 (385
mg).
[0700] MS (m/z): 363 [M+H].sup.+
(2) A treatment was carried out in a manner similar to Example 37-1
(3) using Compound 3 (385 mg) to obtain Compound 4 (268 mg).
[0701] MS (m/z): 263 [M+H].sup.+
(3) A treatment was carried out in a manner similar to Example 39
(1) using Compound 4 (268 mg) and Compound 5 (400 mg) to obtain
Compound 6 (80 mg).
[0702] MS (m/z): 604 [M+H].sup.+
(4) A treatment was carried out in a manner similar to Example 6
(7) using Compound 6 (79 mg) to obtain Compound 7 (28 mg).
[0703] MS (m/z): 446 [M+H].sup.+
Example 37-1
##STR00485## ##STR00486##
[0704] (1) Compound 1 (18.5 g), Compound 2 (20 g) and potassium
carbonate (16.35 g) were added to dimethylsulfoxide (280 mL), and
the mixture was stirred at 90.degree. C. overnight. After the
reaction solution was cooled, water and ethyl acetate were added to
carry out a liquid separation. The organic layer was separated,
washed with saturated brine, and dried over anhydrous magnesium
sulfate. The solvent was distilled off under reduced pressure. To
the obtained residue were added n-hexane and ethyl acetate, and the
mixture was stirred, and subsequently, the solid was collected by
filtration to obtain Compound 3 (23.21 g).
[0705] MS (m/z): 292 [M+H].sup.+
(2) Compound 4 (7.44 g) and sodium acetate (4.48 g) were mixed in
water (15.2 mL), and the mixture was stirred at 95.degree. C. for
30 minutes and then cooled. Compound 3 (4 g) was dissolved in 28%
aqueous ammonia and methanol (200 mL), and the above-prepared
reaction solution was added, and the mixture was stirred at room
temperature overnight. The reaction solution was concentrated under
reduced pressure, and ethyl acetate and water were added to carry
out a liquid separation. The organic layer was separated, washed
with saturated brine, and dried over anhydrous magnesium sulfate.
The solvent was distilled off under reduced pressure. After the
obtained residue was purified by NH-silica gel column
chromatography (chloroform:methanol=20:1), the obtained solid was
washed with diisopropyl ether, filtered and dried to obtain
Compound 5 (4.14 g).
[0706] MS (m/z): 398 [M+H].sup.+
(3) To Compound 5 (4.14 g) was added trifluoroacetic acid (21 mL),
and the mixture was stirred at room temperature for 30 minutes. To
the reaction solution was added diethyl ether (150 mL), and the
mixture was stirred for 10 minutes. The deposited solid was
collected by filtration, washed with diethyl ether and dried to
obtain Compound 6 (6.33 g).
[0707] MS (m/z): 298 [M+H].sup.+
(4) Compound 6 (1.50 g) and triethylamine (1.47 mL) were mixed in
tetrahydrofuran (15 mL), benzyl chloroformate (0.63 mL) was added
under ice cooling, and the mixture was stirred at room temperature
overnight. Water and ethyl acetate were added to the reaction
solution to carry out a liquid separation. The organic layer was
separated, washed with a saturated aqueous sodium hydrogen
carbonate solution and water, and dried over anhydrous sodium
sulfate. The solvent was distilled off under reduced pressure. To
the obtained solid residue was added methanol, and the solid was
collected by filtration to obtain Compound 7 (709 mg).
[0708] MS (m/z): 432 [M+H].sup.+
(5) A treatment was carried out in a manner similar to Example 6
(2) using Compound 7 (889 mg) to obtain Compound 8 (1.117 g).
[0709] MS (m/z): 562 [M+H].sup.+
(6) A treatment was carried out in a manner similar to Example 18-1
(2) using Compound 8 (1.11 g) to obtain Compound 9 (833 mg).
[0710] MS (m/z): 428 [M+H].sup.+
(7) Under a nitrogen atmosphere, palladium acetate (2.7 mg),
2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl
(X-PHOS) (17.3 mg) and water (1.1 .mu.L) were added to 1,4-dioxane
(1.7 mL), and the mixture was stirred at 80.degree. C. for 2
minutes. Separately, Compound 9 (170 mg), Compound 10 (153 mg) and
cesium carbonate (197 mg) were mixed under a nitrogen atmosphere,
the above prepared solution was added at 80.degree. C., and
subsequently the mixture was stirred at 100.degree. C. overnight.
The reaction solution was filtered through Celite, and the filtrate
was concentrated under reduced pressure. The obtained residue was
purified by silica gel column chromatography (n-hexane:ethyl
acetate=95:5 to 70:30) to obtain Compound 11 (163 mg).
[0711] MS (m/z): 618 [M+H].sup.+
(8) A treatment was carried out in a manner similar to the Example
19-1 (2) using Compound 11 (163 mg) to obtain Compound 12 (73
mg).
[0712] MS (m/z): 432 [M+H].sup.+
Examples 37-2 to 37-6
[0713] A treatment was carried out in a manner similar to the
Example 37-1 to obtain compounds of Examples 37-2 to 37-6 in Table
18 below.
TABLE-US-00018 TABLE 18 Example Intermediate 1 Intermediate 2 37-2
##STR00487## ##STR00488## 37-3 ##STR00489## ##STR00490## 37-4
##STR00491## ##STR00492## 37-5 ##STR00493## ##STR00494## 37-6
##STR00495## ##STR00496## MS Example Product (m/z) 37-2
##STR00497## 446 [M + H].sup.+ 37-3 ##STR00498## 446 [M + H].sup.+
37-4 ##STR00499## 446 [M + H].sup.+ 37-5 ##STR00500## 450 [M +
H].sup.+ 37-6 ##STR00501## 464 [M + H].sup.+
Example 38-1
##STR00502## ##STR00503##
[0714] (1) A treatment was carried out in a manner similar to the
Example 37-1 (1) using Compound 1 (1.0 g) and Compound 2 (818 mg)
to obtain Compound 3 (1.457 g).
[0715] MS (m/z): 289 [M+H].sup.+
(2) A treatment was carried out in a manner similar to Reference
Example 7-1 (4) using Compound 3 (4.0 g) to obtain Compound 4 (4.23
g).
[0716] MS (m/z): 322 [M+H].sup.+
(3) A treatment was carried out in a manner similar to Reference
Example 7-1 (5) using Compound 4 (2.23 g) to obtain Compound 5
(2.51 g).
[0717] MS (m/z): 306 [M+H].sup.+
(4) A treatment was carried out in a manner similar to the Example
1-1 (1) using Compound 5 (2.94 g) and Compound 6 (1.99 g) to obtain
Compound 7 (345 mg).
[0718] MS (m/z): 372 [M+H].sup.+
(5) A treatment was carried out in a manner similar to the Example
6 (2) using Compound 7 (337 mg) to obtain Compound 8 (422 mg).
[0719] MS (m/z): 502 [M+H].sup.+
(6) To Compound 8 (416 mg) was added a 4N hydrochloric
acid-1,4-dioxane solution (4 mL), and the mixture was stirred at
room temperature for 30 minutes. To the reaction solution was added
diethyl ether, and the deposited solid was collected by filtration,
washed with diethyl ether and then dried to obtain Compound 9 (345
mg).
[0720] MS (m/z): 402 [M+H].sup.+
(7) Compound 9 (338 mg), Compound 10 (290 mg),
tris(dibenzylideneacetone)dipalladium(0) (33 mg),
2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl
(X-PHOS) (33 mg) and cesium carbonate (928 mg) were added to
toluene (4 mL) under a nitrogen atmosphere, and the mixture was
stirred at 80.degree. C. overnight. The reaction solution was
filtered using NH-silica gel, and the filtrate was purified by
silica gel column chromatography (n-hexane:ethyl acetate=75:25 to
50:50) to obtain Compound 11 (156 mg).
[0721] MS (m/z): 592 [M+H].sup.+
(8) A treatment was carried out in a manner similar to the Example
19-1 (2) using Compound 11 (150 mg) to obtain Compound 12 (42
mg).
[0722] MS (m/z): 406 [M+H].sup.+
Examples 38-2 to 38-5
[0723] A treatment was carried out in a manner similar to the
Example 38-1 to obtain compounds of Examples 38-2 to 38-5 in Table
19 below.
TABLE-US-00019 TABLE 19 Example Intermediate 1 Intermediate 2
Intermediate 3 38-2 ##STR00504## ##STR00505## ##STR00506## 38-3
##STR00507## ##STR00508## ##STR00509## 38-4 ##STR00510##
##STR00511## ##STR00512## 38-5 ##STR00513## ##STR00514##
##STR00515## Example Product MS (m/z) 38-2 ##STR00516## 404 [M +
H].sup.+ 38-3 ##STR00517## 406 [M + H].sup.+ 38-4 ##STR00518## 406
[M + H].sup.+ 38-5 ##STR00519## 418 [M + H].sup.+
Example 39
##STR00520##
[0724] (1) Compound 1 (330 mg) was dissolved in dimethylsulfoxide
(7 mL), and Compound 2 (290 mg) and potassium carbonate (140 mg)
were added, and the mixture was stirred at 100.degree. C.
overnight. Water and ethyl acetate were added to the reaction
solution to carry out a liquid separation. The organic layer was
separated, washed with saturated brine, and dried over anhydrous
magnesium sulfate. The solvent was distilled off under reduced
pressure. The obtained residue was purified by silica gel column
chromatography (n-hexane:ethyl acetate=78:22 to 63:37) to obtain
Compound 3 (263 mg).
[0725] MS (m/z): 590 [M+H].sup.+
(2) Lithium aluminum hydride (16 mg) was suspended in
tetrahydrofuran (2 mL), and a solution of Compound 3 (256 mg) in
tetrahydrofuran (3 mL) was added dropwise at room temperature.
After the mixture was stirred for 1 hour, additional lithium
aluminum hydride (16 mg) was added portionwise, and the mixture was
further stirred for 30 minutes. To the reaction solution were added
sodium sulfate (0.2 g) and water (0.2 g) under ice cooling, and the
mixture was stirred at room temperature for 30 minutes. The
insoluble matter was filtered, and the filtrate was concentrated
under reduced pressure. The obtained residue was purified by silica
gel column chromatography (n-hexane:ethyl acetate=70:30 to 25:75)
to obtain Compound 4 (218 mg).
[0726] MS (m/z): 548 [M+H].sup.+
(3) A treatment was carried out in a manner similar to Example 7
(2) using Compound 4 (214 mg) to obtain Compound 5 (54 mg).
[0727] MS (m/z): 418 [M+H].sup.+
Example 40-1
##STR00521##
[0728] (1) Compound 1 (200 mg), Compound 2 (123 mg),
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (178
mg) and N,N-dimethylaminopyridine (DMAP) (6 mg) were added to
dimethylacetamide (5 mL), and the mixture was stirred at room
temperature for two days. Ethyl acetate and a 10% aqueous citric
acid solution were added to the reaction solution to carry out a
liquid separation. The organic layer was separated, washed with
water and saturated brine, and dried over anhydrous sodium sulfate.
The solvent was distilled off under reduced pressure. After the
obtained residue was purified by silica gel column chromatography
(n-hexane:ethyl acetate=100:0 to 30:70), diisopropyl ether and
n-hexane were added, and the solid was collected by filtration to
obtain Compound 3 (191 mg).
[0729] MS (m/z): 546 [M+H].sup.+
(2) Compound 3 (157 mg) was dissolved in methanol (6 mL) and to
this was added 1N hydrochloric acid (2 mL), and the mixture was
stirred at room temperature overnight. The reaction solution was
concentrated under reduced pressure, and an aqueous saturated
sodium hydrogen carbonate solution, ethyl acetate and
tetrahydrofuran were added to the obtained residue under ice
cooling to carry out a liquid separation. The organic layer was
separated, washed with saturated brine, and dried over anhydrous
sodium sulfate. The solvent was distilled off under reduced
pressure. After the obtained residue was purified by silica gel
column chromatography (n-hexane:ethyl acetate=100:0 to 80:20),
isopropyl ether and n-hexane were added, and the solid was
collected by filtration to obtain Compound 4 (75 mg) and Compound 5
(20 mg).
[0730] Compound 4 MS (m/z): 506 [M+H].sup.+
[0731] Compound 5 MS (m/z): 446 [M+H].sup.+
Example 40-2
[0732] A treatment was carried out in a manner similar to the
Example 40-1 to obtain a compound of Example 40-2 in Table 20
below.
TABLE-US-00020 TABLE 20 Example Starting material 1 Starting
material 2 40-2 ##STR00522## ##STR00523## Example Product MS (m/z)
40-2 ##STR00524## 596 [M + H].sup.+
Example 41-1
##STR00525##
[0733] (1) Compound 1 (200 mg), Compound 2 (122 mg),
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (178
mg) and 1-hydroxybenzotriazole (125 mg) were added to
dimethylformamide (5 mL), and the mixture was stirred at room
temperature overnight. Ethyl acetate, n-hexane and water were added
to the reaction solution to carry out a liquid separation. The
organic layer was separated, washed with water and saturated brine,
and dried over anhydrous sodium sulfate. The solvent was distilled
off under reduced pressure. After the obtained residue was purified
by silica gel column chromatography (n-hexane:ethyl acetate=100:0
to 90:10), diisopropyl ether and n-hexane were added, and the solid
was collected by filtration to obtain Compound 3 (241 mg).
[0734] MS (m/z): 545 [M+H].sup.+
(2) Compound 3 (164 mg) was dissolved in 1,4-dioxane (5 mL) and
concentrated hydrochloric acid (5 mL), and the mixture was stirred
at room temperature for 6 hours. A saturated aqueous sodium
hydrogen carbonate solution was added under ice cooling, and ethyl
acetate and tetrahydrofuran were further added to carry out a
liquid separation. The organic layer was separated, washed with
saturated brine, and dried over anhydrous sodium sulfate. The
solvent was distilled off under reduced pressure. To the obtained
residue were added diisopropyl ether and isopropyl alcohol, and the
solid was collected by filtration to obtain Compound 4 (58 mg).
[0735] MS (m/z): 505 [M+H].sup.+
Examples 41-2 to 41-3
[0736] A treatment was carried out in a manner similar to the
Example 41-1 to obtain compounds of Examples 41-2 and 41-3 in Table
21 below.
TABLE-US-00021 TABLE 21 Example Starting material 1 Starting
material 2 41-2 ##STR00526## ##STR00527## 41-3 ##STR00528##
##STR00529## Example Product MS (m/z) 41-2 ##STR00530## 519 [M +
H].sup.+ 41-3 ##STR00531## 519 [M + H].sup.+
Example 42
##STR00532##
[0737] (1) To a solution of Compound 1 (200 mg) in toluene (10 mL)
were added sequentially imidazole (153 mg), triphenylphosphine (590
mg) and iodine (457 mg), and the mixture was stirred at room
temperature for 30 minutes. The reaction solution was diluted with
ethyl acetate, to this was added an aqueous sodium sulfite
solution, and the mixture was stirred. The organic layer was
separated, washed with saturated brine, and dried over anhydrous
sodium sulfate. The solvent was distilled off under reduced
pressure.
[0738] To a solution of Compound 2 (180 mg) in
N,N-dimethylformamide (4 mL) was added 60% sodium hydride (43 mg)
under ice cooling, and the mixture was stirred at room temperature
for 30 minutes. Then, a solution of the above residue in
N,N-dimethylformamide (2 mL) was added, and the mixture was stirred
at room temperature overnight. To the reaction solution was added a
saturated aqueous ammonium chloride solution, and then ethyl
acetate and water were added to carry out a liquid separation. The
organic layer was separated, washed with water, and dried over
anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure. The obtained residue was purified by silica gel
column chromatography (n-hexane:ethyl acetate=67:33 to 40:60) to
obtain Compound 3 (44 mg).
[0739] MS (m/z): 405 [M+H].sup.+
(2) Compound 3 (50 mg) was dissolved in 4N hydrochloric
acid-1,4-dioxane solution (1 mL), and the mixture was stirred at
room temperature overnight. The reaction solution was concentrated
under reduced pressure, the obtained residue was dissolved in
dimethylsulfoxide (1 mL), potassium carbonate (51 mg) and
6-bromonicotinaldehyde (30 mg) were added, and the mixture was
stirred at 100.degree. C. for 3 hours. After the reaction solution
was cooled, ethyl acetate and water were added to carry out a
liquid separation. The organic layer was separated, washed with
water, and dried over anhydrous sodium sulfate. The solvent was
distilled off under reduced pressure.
[0740] Compound 4 (100 mg) and sodium acetate (71 mg) were added to
water (1 mL), and the mixture was stirred at 95.degree. C. for 30
minutes. This was cooled to room temperature, to this were added a
solution of the above residue in 25% aqueous ammonia (1 mL) and
methanol (3 mL), and the mixture was stirred at room temperature
overnight. Ethyl acetate and water to the reaction solution were
added to carry out a liquid separation. The organic layer was
separated, washed with water, and dried over anhydrous sodium
sulfate. The solvent was distilled off under reduced pressure. The
obtained residue was purified by thin layer silica gel
chromatography (chloroform:methanol=9:1) to obtain Compound 5 (30
mg).
[0741] MS (m/z): 516 [M+H].sup.+
(3) A treatment was carried out in a manner similar to Example 18-1
(2) using Compound 5 (30 mg) to obtain Compound 6 (18.9 mg).
[0742] MS (m/z): 426 [M+H].sup.+
Example 43-1
##STR00533##
[0743] (1) Compound 1 (589 mg), Compound 2 (390 mg) and potassium
carbonate (371 mg) were added to dimethylsulfoxide (8 mL), and the
mixture was stirred at 100.degree. C. overnight. Water and ethyl
acetate were added to the reaction solution to carry out a liquid
separation. The organic layer was separated, washed with saturated
brine, and dried over anhydrous magnesium sulfate. The solvent was
distilled off under reduced pressure. The residue was purified by
silica gel column chromatography (n-hexane:ethyl acetate=85:15 to
70:30) to obtain Compound 3 (467 mg).
[0744] MS (m/z): 591 [M+H].sup.+
(2) A treatment was carried out in a manner similar to Example 1-1
(2) using Compound 3 (467 mg) to obtain Compound 4 (446 mg).
[0745] MS (m/z): 577 [M+H].sup.+
(3) A treatment was carried out in a manner similar to Example 7
(2) using Compound 4 (440 mg) to obtain Compound 5 (292 mg).
[0746] MS (m/z): 447 [M+H].sup.+
Examples 43-2 to 43-7
[0747] A treatment was carried out in a manner similar to the
Example 43-1 to obtain compounds of Examples 43-2 to 43-7 in Table
22 below.
TABLE-US-00022 TABLE 22 Example Starting material 1 Starting
material 2 43-2 ##STR00534## ##STR00535## 43-3 ##STR00536##
##STR00537## 43-4 ##STR00538## ##STR00539## 43-5 ##STR00540##
##STR00541## 43-6 ##STR00542## ##STR00543## 43-7 ##STR00544##
##STR00545## Example Product MS (m/z) 43-2 ##STR00546## 431 [M +
H].sup.+ 43-3 ##STR00547## 413 [M + H].sup.+ 43-4 ##STR00548## 431
[M + H].sup.+ 43-5 ##STR00549## 445 [M + H].sup.+ 43-6 ##STR00550##
445 [M + H].sup.+ 43-7 ##STR00551## 411 [M + H].sup.+
Example 44-1
##STR00552##
[0748] (1) A treatment was carried out in a manner similar to the
Example 43-1 (1) using Compound 1 (1 g) and Compound 2 (0.545 g) to
obtain Compound 3 (1.95 g).
[0749] MS (m/z): 457 [M+H].sup.+
(2) A treatment was carried out in a manner similar to the Example
18-1 (3) using Compound 3 (0.246 g) and Compound 4 (0.179 g) to
obtain Compound 5 (0.253 g).
[0750] MS (m/z): 605 [M+H].sup.+
(3) A treatment was carried out in a manner similar to the Example
1-1 (2) using Compound 5 (0.252 g) to obtain Compound 6 (0.242
g).
[0751] MS (m/z): 591 [M+H].sup.+
(4) A treatment was carried out in a manner similar to the Example
7 (2) using Compound 6 (0.241 g) to obtain Compound 7 (0.164
g).
[0752] MS (m/z): 461 [M+H].sup.+
Examples 44-2 to 44-11
[0753] A treatment was carried out in a manner similar to the
Example 44-1 to obtain compounds of Examples 44-2 to 44-11 in Table
23 below.
TABLE-US-00023 TABLE 23 Example Intermediate 1 Intermediate 2 44-2
##STR00553## ##STR00554## 44-3 ##STR00555## ##STR00556## 44-4
##STR00557## ##STR00558## 44-5 ##STR00559## ##STR00560## 44-6
##STR00561## ##STR00562## 44-7 ##STR00563## ##STR00564## 44-8
##STR00565## ##STR00566## 44-9 ##STR00567## ##STR00568## 44-10
##STR00569## ##STR00570## 44-11 ##STR00571## ##STR00572## Example
Product MS (m/z) 44-2 ##STR00573## 461 [M + H].sup.+ 44-3
##STR00574## 461 [M + H].sup.+ 44-4 ##STR00575## 461 [M + H].sup.+
44-5 ##STR00576## 465 [M + H].sup.+ 44-6 ##STR00577## 481/483 [M +
H].sup.+ 44-7 ##STR00578## 447 [M + H].sup.+ 44-8 ##STR00579## 477
[M + H].sup.+ 44-9 ##STR00580## 443 [M + H].sup.+ 44-10
##STR00581## 447 [M + H].sup.+ 44-11 ##STR00582## 447 [M +
H].sup.+
Example 45-1
##STR00583##
[0754] (1) Compound 1 (395 mg), Compound 2 (500 mg),
tris(dibenzylideneacetone)dipalladium(0) (22 mg),
4,5-bis(diphenylphosphino)-9,9-dimethyl xanthene (Xantphos) (41 mg)
and sodium t-butoxide (342 mg) were added to toluene (10 mL), and
the mixture was stirred under a nitrogen atmosphere at 100.degree.
C. for 3 hours. Ethyl acetate and water were added to the reaction
solution to carry out a liquid separation. The organic layer was
separated, washed with saturated brine, and dried over anhydrous
sodium sulfate. The solvent was distilled off under reduced
pressure. The residue was purified by silica gel column
chromatography (n-hexane:ethyl acetate=95:5 to 80:20) to obtain
Compound 3 (121 mg).
[0755] MS (m/z): 618 [M+H].sup.+
(2) A treatment was carried out in a manner similar to the Example
6 (7) using Compound 3 (120 mg) to obtain Compound 4 (34 mg).
[0756] MS (m/z): 460 [M+H].sup.+
Examples 45-2 to 45-3
[0757] A treatment was carried out in a manner similar to the
Example 45-1 to obtain compounds of Examples 45-2 and 45-3 in Table
24 below.
TABLE-US-00024 TABLE 24 Example Starting material 1 Starting
material 2 45-2 ##STR00584## ##STR00585## 45-3 ##STR00586##
##STR00587## Example Product MS (m/z) 45-2 ##STR00588## 461 [M +
H].sup.+ 45-3 ##STR00589## 432 [M + H].sup.+
Example 46-1
##STR00590## ##STR00591##
[0758] (1) Compound 1 (5 g) and 2,6-lutidine (5.13 mL) were
dissolved in methylene chloride (50 mL), trifluoromethanesulfonic
anhydride (9.88 mL) was added dropwise under ice cooling over 30
minutes, and the mixture was stirred at room temperature for 1
hour. Additional trifluoromethanesulfonic anhydride (2.4 mL) was
added dropwise, and the mixture was stirred at room temperature for
3 hours. After the reaction solution was concentrated under reduced
pressure, the obtained residue was purified by silica gel column
chromatography (n-hexane:ethyl acetate=90:10) to obtain Compound 2
(5.44 g).
[0759] MS (m/z): 303 [M+H].sup.+
(2) A treatment was carried out in a manner similar to the Example
9 (2) using Compound 2 (5.4 g) to obtain Compound 3 (4.42 g).
[0760] MS (m/z): 281 [M+H].sup.+
(3) A treatment was carried out in a manner similar to the Example
7 (1) using Compound 3 (4.4 g) and Compound 4 (6.15 g) to obtain
Compound 5 (6.06 g).
[0761] MS (m/z): 496 [M+H].sup.+
(4) Compound 5 (5.73 g) and 10% palladium-carbon (0.57 g) were
mixed in ethanol (115 mL), and the mixture was stirred under a
hydrogen atmosphere at room temperature for 6 hours. The reaction
solution was filtered, and the filtrate was concentrated under
reduced pressure. The obtained residue was purified by silica gel
column chromatography (n-hexane:ethyl acetate=90:10 to 66:34) to
obtain Compound 6 (5.35 g).
[0762] MS (m/z): 498 [M+H].sup.+
(5) A treatment was carried out in a manner similar to the Example
10 (2) using Compound 6 (0.906 g) to obtain Compound 7 (446 mg) and
Compound 8 (176 mg).
[0763] MS (m/z): 456 [M+H].sup.+
##STR00592##
(6) Compound 8 (165 mg) was dissolved in methylene chloride (3.3
mL), then diisopropyl ethyl amine (126 .mu.L) and methanesulfonyl
chloride (42 .mu.L) were added under ice cooling, and the mixture
was stirred at room temperature for 50 minutes. Diethyl ether and
water were added to the reaction solution to carry out a liquid
separation. The organic layer was separated, washed with water, and
dried over anhydrous magnesium sulfate. The solvent was distilled
off under reduced pressure. Compound 9 (83 mg) was dissolved in
N,N-dimethylformamide (1.6 mL), 60% sodium hydride (24.6 mg) was
added under ice cooling, and the mixture was stirred at room
temperature for 30 minutes. To this was added a solution of the
above residue in N,N-dimethylformamide (1.6 mL), and the mixture
was stirred at 70.degree. C. for 3 hours. After the reaction
solution was cooled, water and ethyl acetate were added to carry
out a liquid separation. The organic layer was separated, washed
with water and saturated brine, and dried over anhydrous magnesium
sulfate. The solvent was distilled off under reduced pressure. The
obtained residue was purified by silica gel column chromatography
(n-hexane:ethyl acetate=95:5 to 80:20) to obtain Compound 10 (107
mg).
[0764] MS (m/z): 590 [M+H].sup.+
(7) A treatment was carried out in a manner similar to Example 1-1
(2) and Example 7 (2) using Compound 10 (97 mg) to obtain Compound
11 (79 mg).
[0765] MS (m/z): 446 [M+H].sup.+
Examples 46-2 to 46-7
[0766] A treatment was carried out in a manner similar to the
Example 46-1 to obtain compounds of Examples 46-2 to 46-7 in Table
25 below.
TABLE-US-00025 TABLE 25 Example Intermediate 1 Intermediate 2 46-2
##STR00593## ##STR00594## 46-3 ##STR00595## ##STR00596## 46-4
##STR00597## ##STR00598## 46-5 ##STR00599## ##STR00600## 46-6
##STR00601## ##STR00602## 46-7 ##STR00603## ##STR00604## Example
Product MS (m/z) 46-2 ##STR00605## 446 [M + H].sup.+ 46-3
##STR00606## 460 [M + H].sup.+ 46-4 ##STR00607## 460 [M + H].sup.+
46-5 ##STR00608## 464 [M + H].sup.+ 46-6 ##STR00609## 480/482 [M +
H].sup.+ 46-7 ##STR00610## 444 [M + H].sup.+
Example 47-1
##STR00611##
[0767] (1) A treatment was carried out in a manner similar to the
Example 18-1 (3) using Compound 1 (91 mg) and Compound 2 (61 mg) to
obtain Compound 3 (70 mg).
[0768] MS (m/z): 591 [M+H].sup.+
(2) A treatment was carried out in a manner similar to the Example
1-1 (2) and Example 7 (2) using Compound 3 (67 mg) to obtain
Compound 4 (41 mg).
[0769] MS (m/z): 447 [M+H].sup.+
Example 47-2
[0770] A treatment was carried out in a manner similar to the
Example 47-1 to obtain a compound of Example 47-2 in Table 26
below.
TABLE-US-00026 TABLE 26 Example Intermediate 1 Intermediate 2 47-2
##STR00612## ##STR00613## Example Product MS (m/z) 47-2
##STR00614## 447 [M + H].sup.+
Example 48
##STR00615##
[0771] (1) Compound 1 (see US2010/267689) (320 mg) and
2,6-di-t-butyl-4-methylpyridine (197 .mu.L) were dissolved in
methylene chloride (8 mL), trifluoromethanesulfonic anhydride (238
.mu.L) was added, and the mixture was stirred at room temperature
overnight. Water was added to the reaction solution to carry out a
liquid separation. The organic layer was separated, and the solvent
was distilled off under reduced pressure. To the obtained residue
was added diisopropyl ether to be mixed. The insoluble substance
was filtered out. The filtrate was concentrated under reduced
pressure, and the obtained residue was purified by silica gel
column chromatography (n-hexane:ethyl acetate=95:5 to 85:15) to
obtain Compound 2 (181 mg).
[0772] MS (m/z): 393 [M+H].sup.+
(2) A treatment was carried out in a manner similar to the Example
9 (2) using Compound 2 (180 mg) to obtain Compound 3 (202 mg).
[0773] MS (m/z): 388 [M+NH4].sup.+
(3) A treatment was carried out in a manner similar to the Example
7 (1) using Compound 3 (210 mg) and Compound 4 (150 mg) to obtain
Compound 5 (56 mg).
[0774] MS (m/z): 586 [M+H].sup.+
(4) Compound 5 (56 mg) was dissolved in ethanol (2.2 mL) and ethyl
acetate (0.56 mL), 10% palladium-carbon (11 mg) was added, and the
mixture was stirred under a hydrogen atmosphere at room temperature
for 6 hours. The reaction solution was filtered through a
membrane-filter, and the filtrate was concentrated under reduced
pressure to obtain Compound 6 (55 mg).
[0775] MS (m/z): 588 [M+H].sup.+
(5) A treatment was carried out in a manner similar to Example 1-1
(2) and Example 7 (2) using Compound 6 (54 mg) to obtain Compound 7
(28 mg).
[0776] MS (m/z): 430 [M+H].sup.+
Example 49
##STR00616## ##STR00617##
[0777] (1) Compound 1 (4.5 g) was dissolved in
N,N-dimethylformamide (45 mL), to this was added sodium hydride
(1.37 g) under ice cooling, and the mixture was stirred under a
nitrogen stream for 30 minutes. To this was added dropwise Compound
2 (5.09 g), and the mixture was stirred at 0.degree. C. for 30
minutes and then at room temperature for 1 hour. Water and ethyl
acetate were added to the reaction solution to carry out a liquid
separation. The organic layer was separated, washed with saturated
brine, and dried over anhydrous magnesium sulfate. The solvent was
distilled off under reduced pressure. The obtained residue was
purified by silica gel column chromatography (n-hexane:ethyl
acetate=95:5 to 65:35) to obtain Compound 3 (3.13 g).
[0778] MS (m/z): 257 [M+H].sup.+
(2) 60% Sodium hydride (537 mg) was suspended in dimethylsulfoxide
(4 mL), and trimethylsulfonium iodide (2.95 g) was added, and the
mixture was stirred at room temperature for 1 hour. To this was
added dropwise a solution of Compound 3 (3.13 g) in
dimethylsulfoxide (2 mL), and the mixture was stirred at room
temperature for 3 days. Water and diethyl ether were added to the
reaction solution to carry out a liquid separation. The organic
layer was separated and washed with saturated brine, and then the
solvent was distilled off under reduced pressure. The obtained
residue was purified by silica gel column chromatography
(n-hexane:ethyl acetate=90:10 to 65:35) to obtain Compound 4 (898
mg).
[0779] MS (m/z): 271 [M+H].sup.+
(3) Compound 4 (100 mg) was dissolved in acetic acid (2 mL), and
platinum oxide (10 mg) was added under a nitrogen atmosphere, and
the mixture was stirred under a hydrogen atmosphere at room
temperature for 8 hours. The reaction solution was filtered through
a membrane-filter, and the filtrate was concentrated under reduced
pressure. The obtained residue was purified by silica gel column
chromatography (n-hexane:ethyl acetate=90:10 to 35:65) to obtain
Compound 5 (41 mg).
[0780] MS (m/z): 273 [M+H].sup.+
(4) Compound 5 (355 mg) was dissolved in trifluoroacetic acid (0.3
mL), water (1 mL) and tetrahydrofuran (3 mL), and the mixture was
stirred at 65.degree. C. for 3 hours. Water, an aqueous sodium
hydrogen carbonate solution and ethyl acetate were added to the
reaction solution to carry out a liquid separation. The organic
layer was separated and washed with saturated brine, and then the
solvent was distilled off under reduced pressure. The obtained
residue was purified by silica gel column chromatography
(n-hexane:ethyl acetate=90:10 to 65:35) to obtain Compound 6 (242
mg).
[0781] MS (m/z): 229 [M+H].sup.+
(5) Compound 6 (230 mg) and
N-phenylbis(trifluoromethanesulfonamide) (719 mg) were dissolved in
tetrahydrofuran (5 mL), 0.5N potassium hexamethyldisilazane (4.03
mL) was added dropwise under a nitrogen atmosphere at -78.degree.
C., and the mixture was stirred for 1 hour. Water, an aqueous
saturated ammonium chloride solution and ethyl acetate were added
to the reaction solution to carry out a liquid separation. The
organic layer was separated and washed with saturated brine, and
subsequently the solvent was distilled off under reduced pressure.
The obtained residue was purified by silica gel column
chromatography (n-hexane:ethyl acetate=96:4 to 80:20) and NH-silica
gel column chromatography (n-hexane:ethyl acetate=98:2 to 92:8) to
obtain Compound 7 (623 mg).
[0782] MS (m/z): 361 [M+H].sup.+
(6) A treatment was carried out in a manner similar to the Example
9 (2) using Compound 7 to obtain Compound 8.
[0783] MS (m/z): 339 [M+H].sup.+
(7) A treatment was carried out in a manner similar to the Example
7 (1) using Compound 8 to obtain Compound 10.
[0784] MS (m/z): 554 [M+H].sup.+
(8) Compound 10 (257 mg) was suspended in methanol (4 mL) and
tetrahydrofuran (2 mL), 10% palladium-carbon (26 mg) was added
under a nitrogen atmosphere, and the mixture was stirred under a
hydrogen atmosphere at room temperature for 5 hours. The reaction
solution was filtered through a membrane-filter, and the filtrate
was concentrated under reduced pressure. The obtained residue was
purified by silica gel column chromatography (n-hexane:ethyl
acetate=80:20 to 60:40) to obtain Compound 11 (220 mg).
[0785] MS (m/z): 556 [M+H].sup.+
(9) A treatment was carried out in a manner similar to the Example
1-1 (2) using Compound 11 (218 mg) to obtain Compound 12 (131
mg).
[0786] MS (m/z): 542 [M+H].sup.+
(10) A treatment was carried out in a manner similar to the Example
7 (2) using Compound 12 (130 mg) to obtain Compound 13 (4.8
mg).
[0787] MS (m/z): 412 [M+H].sup.+
Example 50
[0788] (1)
##STR00618##
[0789] To ethanol (250 mL) was added Compound 1 (10 g), and the
mixture was ice-cooled. Hydrochloric acid gas was blown for 10
minutes. The reaction solution was stirred at room temperature
overnight and subsequently concentrated under reduced pressure to
obtain Compound 2 (12.53 g) as a white powder.
[0790] MS (m/z): 228/230 [M+H].sup.+
(2)
##STR00619##
[0791] Compound 2 (12.53 g) was dissolved in ethanol (94 mL), and a
7N ammonia/methanol solution (31.5 mL) was added dropwise at room
temperature over 5 minutes. After the reaction solution was stirred
at room temperature for 3 hours, an additional 7N ammonia/methanol
solution (15.7 mL) was added, and the mixture was stirred
overnight. The reaction solution was concentrated under reduced
pressure, to the obtained white solid was added diethyl ether, and
the mixture was stirred. Subsequently, the solid was collected by
filtration and dried to obtain Compound 3 (13.25 g) as a white
powder.
[0792] MS (m/z): 199/201 [M+H].sup.+
(3)
##STR00620##
[0793] Compound 3 (13.25 g) was suspended in water (40 mL), and a
5N aqueous sodium hydroxide solution (40 mL) was added, and the
mixture was stirred at room temperature for 3 hours. The deposit
was collected by filtration and washed with water. The obtained
white solid was dissolved in acetone, activated charcoal was added,
and the mixture was stirred for 10 minutes, and subsequently,
filtered through Celite. The filtrate was concentrated under
reduced pressure, and the obtained powder was washed with diethyl
ether, collected by filtration and dried to obtain Compound 4 (9.58
g) as a white powder.
(4)
##STR00621##
[0794] To tetrahydrofuran (6 mL) were added ethyl trifluoroacetate
(598 .mu.L) and hydrazine hydrate (232 .mu.L), and the mixture was
stirred at 65.degree. C. for 1 hour. To the reaction solution was
added Compound 4 (1 g), and the mixture was stirred at 65.degree.
C. for 4.5 hours. Water was added, and the mixture was extracted
with ethyl acetate, washed with saturated brine, and dried over
anhydrous magnesium sulfate. After the mixture was dried and
concentrated under reduced pressure, the obtained solid was
dissolved in ethyl acetate, activated charcoal was added, and the
mixture was stirred. Subsequently, the mixture was filtered out
through Celite. The filtrate was concentrated under reduced
pressure, and the obtained residue was purified by silica gel
column chromatography (n-hexane:ethyl acetate=90:10 to 80:20) to
obtain Compound 5 (1.082 g) as a white solid.
[0795] MS (m/z): 292/294 [M+H].sup.+
(5)
##STR00622##
[0796] Compound 5 (1 g) was dissolved in N,N-dimethylformamide (25
mL), sodium hydride (212 mg) was added under ice cooling, and the
mixture was stirred for 40 minutes. At the same temperature,
2-(chloromethoxy)ethyltrimethylsilane (910 .mu.L) was added, the
temperature was elevated to room temperature, and the mixture was
stirred for 5 hours. An aquous saturated sodium hydrogen carbonate
solution was added, and the mixture was extracted with ethyl
acetate. The organic layer was washed with saturated brine, dried
over anhydrous sodium sulfate and concentrated under reduced
pressure. The obtained residue was purified by silica gel column
chromatography (n-hexane:ethyl acetate=90:10 to 80:20) to obtain a
mixture of Compounds 6a and 6b (10:9) as a colorless liquid.
[0797] MS (m/z): 422/424 [M+H].sup.+
(6)
##STR00623##
[0798] The mixed solution of the mixture of Compounds 6a and 6b
(202 mg), Compound 7 (242 mg), a
[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride
dichloromethane complex (20 mg), N,N-dimethylformamide (5 mL) and a
2N aqueous sodium carbonate solution (950 .mu.L) was stirred at
80.degree. C. for 19 hours. The reaction solution was filtered
through Celite, and to the filtrate was added water, and the
mixture was extracted with ethyl acetate. The extract was washed
with saturated brine, and concentrated. The obtained residue was
purified by silica gel column chromatography (n-hexane:ethyl
acetate=90:10 to 85:15) to obtain a mixture of Compounds 8a and 8b
(278 mg) as a pale yellow solid.
[0799] MS (m/z): 574 [M+H].sup.+
(7)
##STR00624##
[0800] To the mixture of Compounds 8a and 8b (272 mg) were added
trifluoroacetic acid (5.4 mL) and water (540 .mu.L), and the
mixture was stirred at room temperature for 7 hours. The reaction
solution was concentrated under reduced pressure, and to the
obtained solid was added cold methanol, and the mixtue was
sonicated. The obtained suspension was filtered and then washed
with cold methanol to obtain Compound 9 (152 mg) as a white
solid.
[0801] MS (m/z): 444 [M+H].sup.+
(8)
##STR00625##
[0802] To Compound 9 (150 mg) were added tetrahydrofuran (6 mL),
methanol (6 mL), and an 8N aqueous sodium hydroxide solution (0.175
mL), and the mixture was stirred at room temperature overnight. To
the reaction solution were added acetic acid (2 mL) and water (2
mL), and the solution was concentrated under reduced pressure. The
obtained solid was suspended in cold methanol, collected by
filtration and washed with water and methanol. The obtained white
powder was purified using LC-MS, the obtained fraction was
concentrated, and water (3 mL) and methanol (0.5 mL) were added.
Then, the mixture was suspended by sonification, acetic acid (200
.mu.L) was added, and the mixture was stirred. The obtained powder
was collected by filtration, washed with water and methanol and
dried to obtain Compound 10 (27 mg).
[0803] MS (m/z): 430 [M+H].sup.+
Example 51
[0804] (1)
##STR00626##
[0805] Sodium hydride (15.6 g) was suspended in 300 mL of
tetrahydrofuran under a nitrogen stream, and Compound 1 (30 mL) was
added dropwise over 30 minutes under ice cooling. After the mixture
was stirred under ice cooling for 30 minutes, methyl iodide (24.3
mL) was added dropwise, and the mixture was stirred at room
temperature for 16 hours. To the reaction solution was added water,
and the mixture was extracted with ethyl acetate. The extract was
washed with saturated brine, and dried over anhydrous magnesium
sulfate. The solution was concentrated under reduced pressure to
obtain Compound 2 (24.76 g). The obtained Compound 2 (24.76 g) was
dissolved in tetrahydrofuran (320 mL), 1M lithium hydroxide
tri-tert-butoxyaluminum (300 mL) was added dropwise over 45 minutes
under a nitrogen stream at room temperature, and the mixture was
heated at reflux for 2 hours. To the reaction solution was added
saturated brine, and the mixture was filtered through Celite and
washed with ethyl acetate. The filtrate was concentrated under
reduced pressure, to the concentrated residue were added ethyl
acetate and water, and the mixture was extracted with ethyl
acetate. The extract was washed with saturated brine, and dried
over anhydrous magnesium sulfate. After the solution was
concentrated under reduced pressure, the obtained residue was
distilled under reduced pressure to obtain Compound 3 (13.52
g).
[0806] MS (m/z): 175 [M+H].sup.+
(2)
##STR00627##
[0807] Compound 3 (1005 mg), Compound 4 (500 mg) and
triphenylphosphine (1500 mg) were dissolved in tetrahydrofuran (8
mL), a 40% solution of diethyl azodicarboxylate in toluene (2.65
mL) was added, and the mixture was stirred at 80.degree. C. for 3
hours. To the reaction solution was added water, and the mixture
was extracted with ethyl acetate. The extract was washed with
saturated brine, and dried over anhydrous sodium sulfate. After the
solution was concentrated under reduced pressure, the obtained
residue was purified by silica gel column chromatography
(n-hexane:ethyl acetate=93:7 to 90:10) to obtain Compound 5 (810
mg) as a pink liquid.
[0808] MS (m/z): 330/332 [M+H].sup.+
(3)
##STR00628##
[0809] To a mixture of Compounds 6a and 6b (1000 mg), potassium
acetate (700 mg) and bis(pinacolato)diboron (755 mg) was added
1,4-dioxane (24 mL), and the mixture was subjected to nitrogen
substitution. Then, a
[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride
dichloromethane complex (58 mg) and (diphenylphosphino)ferrocene
(40 mg) were added, and the mixture was subjected to nitrogen
substitution again and stirred at 80.degree. C. for 21 hours. To
the reaction solution were added water and ethyl acetate, and the
mixture was stirred and subsequently filtered through Celite. The
filtrate was extracted with ethyl acetate, washed with saturated
brine and dried. After the solution was concentrated under reduced
pressure, the obtained residue was purified by silica gel column
chromatography (n-hexane:ethyl acetate=95:5 to 85:15) to obtain a
mixture of Compounds 7a and 7b (986 mg) as a white solid.
[0810] MS (m/z): 470 [M+H].sup.+
(4)
##STR00629##
[0811] A mixture of the mixture of Compounds 7a and 7b (150 mg),
Compound 5 (135 mg), N,N-dimethylformamide (3 mL) and a 2M aqueous
sodium carbonate solution (0.64 mL) was subjected to nitrogen
substitution, then a
[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride
dichloromethane complex (29 mg) was subsequently added, and the
mixture was stirred at 80.degree. C. for 15 hours. To the reaction
solution was added water, and the mixture was extracted with ethyl
acetate, washed with saturated brine and dried over anhydrous
sodium sulfate. After the solution was concentrated under reduced
pressure, the obtained residue was purified by silica gel column
chromatography (n-hexane:ethyl acetate=95:5 to 90:10) to obtain a
mixture of Compounds 8a and 8b (125 mg) as a pale yellow viscous
material.
[0812] MS (m/z): 593 [M+H].sup.+
(5)
##STR00630##
[0813] To the mixture of Compounds 8a and 8b (125 mg) were added
trifluoroacetic acid (2.5 mL) and water (0.25 mL), and the mixture
was stirred at room temperature for 16 hours. The reaction solution
was concentrated under reduced pressure, the residue was dissolved
in tetrahydrofuran, the solution was neutralized with 1N sodium
hydroxide, and 0.1M phosphate buffer having pH 7 (2 mL) was added.
This was washed with ethyl acetate, and the aqueous layer was
concentrated under reduced pressure. The obtained residue was
purified by silica gel column chromatography (n-hexane:ethyl
acetate=80:20 to 60:40) to obtain Compound 9 (26 mg) as a white
solid.
[0814] MS (m/z): 407 [M+H].sup.+
Example 52
[0815] (1)
##STR00631##
[0816] A reaction was carried out in a manner similar to the
Example 50-(1) using Compound 1 (5 g) to obtain Compound 2 (7.98 g)
as a pale yellow powder.
[0817] MS (m/z): 185/187 [M+H].sup.+
(2)
##STR00632##
[0818] A reaction was carried out in a manner similar to the
Example 50-(2) using Compound 2 (7.98 g) to obtain Compound 3 (6.29
g) as a red powder.
[0819] MS (m/z): 156/158 [M+H].sup.+
(3)
##STR00633##
[0820] A reaction was carried out in a manner similar to the
Example 50-(3) using Compound 3 (6.29 g) to obtain Compound 4 (2.49
g) as a pink powder.
[0821] MS (m/z): 156/158 [M+H].sup.+
(4)
##STR00634##
[0822] A reaction was carried out in a manner similar to the
Example 50-(4) using Compound 4 (2.48 g) to obtain Compound 5 (2.91
g) as a pink powder.
[0823] MS (m/z): 249 [M+H].sup.+
(5)
##STR00635##
[0824] A reaction was carried out in a manner similar to the
Example 50-(5) using Compound 5 (2.91 g) to obtain Compound 6a
(2.18 g) as a colorless solid and Compound 6b (2.09 g) as a
colorless oil.
[0825] MS (m/z): 379/381 [M+H].sup.+
(6)
##STR00636##
[0826] A reaction was carried out in a manner similar to the
Example 50-(6) using Compound 6a (500 mg) and Compound 7 (881 mg)
to obtain Compound 8 (563 mg) as a colorless powder.
[0827] MS (m/z): 575 [M+H].sup.+
(7)
##STR00637##
[0828] A mixture of Compound 8 (563 mg), methanol (5.6 mL),
tetrahydrofuran (9.6 mL) and a 2N aqueous sodium hydroxide solution
(3.92 mL) was stirred at room temperature for 14 hours. After the
mixture was neutralized by addition of acetic acid, the mixture was
concentrated under reduced pressure, to the obtained residue was
added water, the mixture was extracted with ethyl acetate. The
extract was washed with 0.1N phosphate buffer having pH 7, filtered
and concentrated under reduced pressure. The obtained solid was
recrystallized from methanol to obtain Compound 9 (353 mg) as a
colorless powder. Further, the concentrated residue of the mother
liquid was purified by silica gel column chromatography
(chloroform:methanol=100:0 to 96:4) to obtain Compound 9 (67 mg) as
a white solid.
[0829] MS (m/z): 561 [M+H].sup.+
(8)
##STR00638##
[0830] Compound 9 (419 mg) was dissolved in trifluoroacetic acid
(8.38 mL) and water (0.84 mL), and the mixture was stirred at room
temperature for 16 hours. The reaction solution was concentrated
under reduced pressure, and the obtained deposit was washed with
acetonitrile, and recrystallized from acetonitrile. The crystals
were collected by filtration and dried under reduced pressure at
50.degree. C. to obtain Compound 10 (223 mg) as a white solid.
[0831] MS (m/z): 431 [M+H].sup.+
Example 53
[0832] (1)
##STR00639##
[0833] A mixed solution of Compound 1 (1000 mg), Compound 2 (1085
mg), a 2M aqueous sodium carbonate solution (4736 .mu.L) and
N,N-dimethylformamide (20 mL) was subject to nitrogen substitution,
and subsequently a
[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride
dichloromethane complex (193 mg) was added, and the mixture was
stirred at 80.degree. C. overnight. To the reaction solution were
added water and ethyl acetate, and the mixture was stirred at room
temperature for 30 minutes, and filtered through Celite. The
filtrate was extracted with ethyl acetate, and the extract was
washed with water, and dried over anhydrous sodium sulfate. The
solution was concentrated under reduced pressure, and the obtained
residue was purified by silica gel column chromatography
(n-hexane:ethyl acetate=95:5 to 80:20) to obtain Compound 3 (1288
mg) as a colorless solid.
[0834] MS (m/z): 527 [M+H].sup.+
(2)
##STR00640##
[0835] Compound 3 (1285 mg) was dissolved in ethanol (26 mL), and
the mixture was subjected to nitrogen substitution. Subsequently,
palladium carbon (386 mg) was added, and the mixture was stirred
under a hydrogen atmosphere at room temperature for 6 hours. The
reaction solution was filtered through Celite and washed with
tetrahydrofuran. After the filtrate was concentrated under reduced
pressure, the obtained residue was purified by silica gel column
chromatography (n-hexane:ethyl acetate=80:20 to 60:40) to obtain
Compound 4 (966 mg) as a colorless solid.
[0836] MS (m/z): 437 [M+H].sup.+
(3)
##STR00641##
[0837] Compound 5 (20.04 g) and imidazole (15.84 g) were dissolved
in N,N-dimethylformamide (116 mL), tert-butyldimethylsilyl chloride
(19.47 g) was added under ice cooling, and the mixture was stirred
at room temperature for 15 hours. The reaction solution was added
to ice water, and the mixture was extracted with diethyl ether. The
extract was washed with water and saturated brine. The solution was
dried over anhydrous magnesium sulfate, and concentrated under
reduced pressure to obtain Compound 6 (34.94 g) as a colorless
oil.
[0838] MS (m/z): 287 [M+H].sup.+
(4)
##STR00642##
[0839] Compound 6 (34.93 g) was dissolved in tetrahydrofuran (241
mL), a 2N aqueous sodium hydroxide solution (244 mL) was added, and
the mixture was stirred at 70.degree. C. for 15 hours.
Tetrahydrofuran was distilled off under reduced pressure, and the
aqueous solution was washed with n-hexane and diethyl ether. The
aqueous layer was adjusted to pH=4 with a 1N aqueous citric acid
solution, and the mixture was extracted with diethyl ether. The
extract was dried over anhydrous magnesium sulfate and concentrated
under reduced pressure to obtain Compound 7 (26.17 g) as a
colorless solid.
[0840] MS (m/z): 259 [M+H].sup.+
(5)
##STR00643##
[0841] Compound 7 (33.75 g) and Boc.sub.2O (34.2 g) were dissolved
in tert-butanol (338 mL), and 4-dimethylaminopyridine (4.79 g) was
added, and the mixture was stirred at room temperature for 17
hours. After the reaction solution was concentrated under reduced
pressure, the obtained residue was purified by silica gel column
chromatography (n-hexane:ethyl acetate=99:1 to 91:9) to obtain
Compound 8 (40.68 g) as a colorless oil.
[0842] MS (m/z): 315 [M+H].sup.+
(6)
##STR00644##
[0843] A solution of diisopropyl amine (1.94 mL) in tetrahydrofuran
(30 mL) was cooled to -70.degree. C., 2.6M n-butyl lithium (5.3 mL)
was added dropwise, and the mixture was stirred at the same
temperature for 10 minutes. Subsequently, the temperature was
elevated to 0.degree. C. The reaction solution was again cooled to
-70.degree. C., and a solution of Compound 8 (2.9 g) in
tetrahydrofuran (10 mL) was added dropwise. After the mixture was
stirred at the same temperature for 10 minutes, the temperature was
elevated to 0.degree. C. The reaction solution was again cooled to
-70.degree. C., and methoxymethyl chloride (1.4 mL) was added
dropwise. After the mixture was stirred at the same temperature for
30 minutes, the temperature was elevated to room temperature, and
the mixture was stirred for 13 hours. To the reaction solution was
added a saturated aqueous ammonium chloride solution, and the
mixture was extracted with ethyl acetate. The extract was washed
with saturated brine. After the mixture was dried over anhydrous
magnesium sulfate, and concentrated under reduced pressure, and the
obtained residue was purified by silica gel column chromatography
to obtain a cis form of Compound 9 (1.5 g) as a colorless oil.
[0844] MS (m/z): 359 [M+H].sup.+
(7)
##STR00645##
[0845] To Compound 9 (31.56 g) was added a 1M solution of
n-tetrabutylammonium fluoride in tetrahydrofuran (175 mL), and the
mixture was stirred at room temperature for 21 hours. Additionally,
a 1M solution of n-tetrabutylammonium fluoride in tetrahydrofuran
(85 mL) was added, and the mixture was stirred at room temperature
for 4 hours. The reaction solution was concentrated under reduced
pressure, to the obtained residue was added a saturated aqueous
ammonium chloride solution, and the mixture was extracted with
ethyl acetate. The extract was washed with saturated brine, and
dried over anhydrous magnesium sulfate. The extract was
concentrated under reduced pressure, and the obtained residue was
purified by silica gel column chromatography to obtain Compound 10
(18.56 g) as a colorless oil.
[0846] MS (m/z): 245 [M+H].sup.+
(8)
##STR00646##
[0847] A solution of Compound 4 (150 mg), Compound 10 (126 mg),
tributylphosphine (127 .mu.L) and ADDP (130 mg) in tetrahydrofuran
(3 mL) was heated at reflux overnight. The reaction solution was
concentrated under reduced pressure, and the residue was washed
with diethyl ether and filtered. The filtrate was concentrated
under reduced pressure, and the obtained residue was purified by
silica gel column chromatography (n-hexane:ethyl acetate=90:10 to
80:20) to obtain Compound 11 (162 mg) a colorless viscous
material.
[0848] MS (m/z): 663 [M+H].sup.+
(9)
##STR00647##
[0849] Compound 11 (162 mg) was dissolved in trifluoroacetic acid
(3 mL) and water (0.3 mL), and the mixture was stirred at room
temperature overnight. The reaction solution was concentrated under
reduced pressure, to the obtained residue was added acetic acid,
and the mixture was concentrated under reduced pressure. The
residue was crystallized from ethyl acetate, and the obtained solid
was filtered and dried to obtain Compound 12 (96 mg) as an ivory
solid.
[0850] MS (m/z): 477 [M+H].sup.+
Example 54
[0851] (1)
##STR00648##
[0852] A reaction was carried out in a manner similar to the
Example 52-(6) using Compound 1 (207 mg) and Compound 2 (293 mg) to
obtain Compound 3 (252 mg) as a colorless solid.
[0853] MS (m/z): 552 [M+H].sup.+
(2)
##STR00649##
[0854] A reaction was carried out in a manner similar to the
Example 52-(7) using Compound 3 (244 mg) to obtain Compound 4 (223
mg) as a colorless solid.
[0855] MS (m/z): 538 [M+H].sup.+
(3)
##STR00650##
[0856] A reaction was carried out in a manner similar to the
Example 52-(8) using Compound 4 (216 mg) to obtain Compound 5 (157
mg) as a colorless solid.
[0857] MS (m/z): 408 [M+H].sup.+
Example 55
[0858] (1)
##STR00651##
[0859] A reaction was carried out in a manner similar to the
Example 51-(2) using Compound 1 (1000 mg) and Compound 2 (702 mg)
to obtain Compound 3 (534 mg) as a colorless viscous material.
[0860] MS (m/z): 400/402 [M+H].sup.+
(2)
##STR00652##
[0861] A reaction was carried out in a manner similar to the
Example 51-(4) using Compound 3 (200 mg) and a mixture of Compounds
4a and 4b (469 mg) to obtain Compound 5a (151 mg) and Compound 5b
(104 mg) as colorless viscous materials respectively.
[0862] MS (m/z): 663 [M+H].sup.+
(3)
##STR00653##
[0863] A reaction was carried out in a manner similar to the
Example 53-(9) using a mixture of Compound 5a and Compound 5b (250
mg) to obtain Compound 6 (158 mg).
[0864] MS (m/z): 477 [M+H].sup.+
Example 56
[0865] (1)
##STR00654##
[0866] To Compound 2 (4.21 g) were added toluene (100 mL) and
triethylamine (9.9 mL) at room temperature, and the mixture was
stirred for 5 minutes. Subsequently, Compound 1 (5 g) was added,
and the mixture was stirred at room temperature for 5 days. The
reaction solution was filtered through Celite, and the filtrate was
concentrated under reduced pressure. To the obtained residue were
added carbon tetrachloride (66.4 mL) and hydrazine hydrate (1.42
mL), and the mixture was stirred at room temperature overnight. The
reaction solution was diluted with ethyl acetate and filtered
through Celite. The filtrate was concentrated under reduced
pressure, to the obtained residue were added water, ethyl acetate
and a saturated aqueous ammonium chloride solution, and the mixture
was extracted with ethyl acetate. The extract was concentrated
under reduced pressure, and the obtained residue was washed with
diethyl ether and filtered to obtain Compound 3 (928 mg) as a light
pink powder.
[0867] MS (m/z): 195/197 [M+H].sup.+
(2)
##STR00655##
[0868] A reaction was carried out in a manner similar to the
Example 50-(5) using Compound 3 (819 mg) to obtain a mixture of
Compounds 4a and 4b (1.014 g) as colorless crystals.
[0869] MS (m/z): 325/327 [M+H].sup.+
(3)
##STR00656##
[0870] A reaction was carried out in a manner similar to the
Example 52-(6) using the mixture of Compounds 4a and 4b (200 mg)
and Compound 5 (309 mg) to obtain Compound 6a (84 mg) and Compound
6b (78 mg) as colorless powders each.
[0871] MS (m/z): 521 [M+H].sup.+
(4)
##STR00657##
[0872] A reaction was carried out in a manner similar to the
Example 52-(7) using Compound 6a (83 mg) to obtain Compound 7a (77
mg) as a colorless powder. Further, the similar reaction was
carried out using Compound 6b (83 mg) to obtain Compound 7b (69 mg)
as a colorless powder.
[0873] MS (m/z): 507 [M+H].sup.+
(5)
##STR00658##
[0874] A reaction was carried out in a manner similar to the
Example 52-(8) using a mixture of Compounds 7a and 7b (146 mg) to
obtain Compound 8 (94 mg) a colorless powder.
[0875] MS (m/z): 377 [M+H].sup.+
Example 57
##STR00659##
[0877] Compound 1 (73 mg), EDC-HCl (88 mg), HOBt (62 mg), ammonium
chloride (25 mg) and triethylamine (64 .mu.L) were dissolved in
dimethylsulfoxide (1 mL), and the mixture was stirred at room
temperature overnight. To the reaction solution was added water,
and the mixture was extracted with ethyl acetate and washed with
water. After the solution was dried and concentrated under reduced
pressure, the obtained residue was purified by silica gel column
chromatography (chloroform:methanol=97:3 to 90:10) to obtain
Compound 2 (46 mg) as a colorless solid.
[0878] MS (m/z): 476 [M+H].sup.+
Example 58
[0879] (1)
##STR00660##
[0880] A solution of Compound 1 (5 g) in tetrahydrofuran (96 mL)
was cooled to -78.degree. C., a solution of n-butyl lithium in
n-hexane (18.3 mL) was added dropwise over 10 minutes, and the
mixture was stirred at the same temperature for 20 minutes. Then, a
solution of sec-butyl lithium in n-hexane (40.7 mL) was added
dropwise over 10 minutes at the same temperature, and the mixture
was stirred at the same temperature for 1 hour. Further, a solution
of Compound 2 (6.73 g) in tetrahydrofuran (44 mL) was added
dropwise at the same temperature over 20 minutes, and the mixture
was stirred at the same temperature for 3 hours. To the reaction
solution was added dropwise a saturated aqueous ammonia chloride
solution (60 mL), and the temperature was elevated to room
temperature. Water was added, the mixture was extracted with ethyl
acetate, and the extract was washed with saturated brine, and dried
over anhydrous magnesium sulfate. After the solution was
concentrated under reduced pressure, the obtained residue was
purified by silica gel column chromatography
(n-hexane:2-propanol=85:15 to 70:30 and chloroform:methanol=100:0
to 93:7) to obtain Compound 3 (2.207 g) as a colorless powder.
[0881] MS (m/z): 252 [M+H].sup.+
(2)
##STR00661##
[0882] To a solution of Compound 3 (1.944 g) in tetrahydrofuran (57
mL) was added the Burgess reagent, and the mixture was heated at
reflux for 20 hours. The reaction solution was ice cooled, an
aquous saturated sodium hydrogen carbonate solution was added, and
the mixture was extracted with ethyl acetate. The extract was dried
over anhydrous magnesium sulfate and subsequently concentrated
under reduced pressure, and the obtained residue was purified by
silica gel column chromatography (n-hexane:2-propanol=91:9 to
80:20) to obtain Compound 4 (953 mg) as a yellow viscous
material.
[0883] MS (m/z): 234 [M+H].sup.+
(3)
##STR00662##
[0884] To a solution of Compound 4 (953 mg) in methanol (33 mL) was
added palladium carbon (286 mg), and the mixture was stirred under
a hydrogen atmosphere at room temperature for 2.5 hours. The
reaction solution was filtered, and the filtrate was concentrated
under reduced pressure. The obtained residue was washed with
isopropyl ether to obtain Compound 5 (627 mg) as a colorless
powder.
[0885] MS (m/z): 236 [M+H].sup.+
(4)
##STR00663##
[0886] A solution of Compound 5 (915 mg) in tetrahydrofuran (4.2
mL) was ice cooled, and sodium hydride (233 mg) was added, and the
mixture was stirred at the same temperature for 30 minutes. A
solution of benzyl bromide (509 .mu.L) in dimethylsulfoxide (4.2
mL) was then added dropwise at the same temperature, and the
mixture was stirred at room temperature for 3 hours. To the
reaction solution was added water, the mixture was extracted with
ethyl acetate, and the extract was washed with brine. The solution
was dried over anhydrous magnesium sulfate, and concentrated under
reduced pressure to obtain a yellow solid (1.45 g). This yellow
solid (1.26 g) was dissolved in tetrahydrofuran (38 mL), 2N
hydrochloric acid (19 mL) was added, and the mixture was stirred at
50.degree. C. for 19 hours. The reaction solution was concentrated
under reduced pressure, ethyl acetate was added, and the solution
was neutralized with a 1N aqueous sodium hydroxide solution. The
mixture was extracted with ethyl acetate, and the extract was
washed with brine and dried over anhydrous sodium sulfate. The
solution was concentrated under reduced pressure, and the obtained
solid was washed with isopropyl ether and filtered. The obtained
powder was vacuum-dried at 50.degree. C. to obtain Compound 6 (979
mg) as a pale yellow powder.
[0887] MS (m/z): 282 [M+H].sup.+
(5)
##STR00664##
[0888] A solution of Compound 7 (760 mg) in tetrahydrofuran (3 mL)
was ice cooled, and 60% sodium hydride (174 mg) was added, and the
mixture was stirred at room temperature for 30 minutes. Compound 6
(979 mg) was then added, and the mixture was stirred for 17 hours.
The reaction solution was ice cooled, water was added, and the
mixture was extracted with ethyl acetate. The extract was washed
with brine, dried over anhydrous sodium sulfate and concentrated
under reduced pressure. The obtained solid was washed with
isopropyl ether and collected by filtration. The solid was
vacuum-dried at 50.degree. C. to obtain Compound 8 (1.005 g) as a
pale yellow powder. Further, the filtrate was concentrated under
reduced pressure and the obtained residue was purified by silica
gel column chromatography (n-hexane:ethyl acetate=80:20 to 67:33)
to obtain Compound 8 (129 mg) as a pale yellow powder.
[0889] MS (m/z): 338 [M+H].sup.+
(6)
##STR00665##
[0890] To a solution of Compound 8 (1133 mg) of ethyl acetate (23
mL) was added palladium carbon (340 mg), and the mixture was
stirred under a hydrogen atmosphere at room temperature for 3 days.
The reaction solution was filtered, the filtrate was concentrated
under reduced pressure, and the obtained residue was washed with
diethyl ether and vacuum-dried at 50.degree. C. to obtain Compound
9 (497 mg) as a pale yellow powder. Further, the filtrate was
concentrated and treated in a similar procedure to obtain Compound
9 (327 mg).
[0891] MS (m/z): 250 [M+H].sup.+
(7)
##STR00666##
[0892] A suspension of Compound 9 (824 mg) in methylene chloride
(16 mL) was ice cooled, trifluoromethanesulfonic anhydride (695
.mu.L) was added, and triethylamine (691 .mu.L) was then added, and
the mixture was stirred at room temperature for 16 hours. To the
reaction solution was added an aquous saturated sodium hydrogen
carbonate solution, and the mixture was extracted with methylene
chloride. The extract was dried over anhydrous sodium sulfate and
concentrated under reduced pressure. The obtained residue was
purified by silica gel column chromatography (n-hexane:ethyl
acetate=95:5 to 75:25) to obtain Compound 10 (1.214 g) as a pale
yellow oil.
[0893] MS (m/z): 382 [M+H].sup.+
(8)
##STR00667##
[0894] Compound 10 (1214 mg), Compound 11 (889 mg),
(diphenylphosphino)ferrocene (53 mg) and potassium acetate (937 mg)
were added to 1,4-dioxane (16 mL), and the mixture was subjected to
nitrogen substitution. A
[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride
dichloromethane complex (78 mg) was then added, and the mixture was
subjected to nitrogen substitution again, and stirred at 80.degree.
C. for 16 hours. To the reaction solution was added water and ethyl
acetate, and the mixture was stirred and filtered through Celite.
After the filtrate was extracted with ethyl acetate, the extract
was washed with saturated brine and dried. After concentration
under reduced pressure, the obtained residue was purified by diol
silica gel column chromatography (n-hexane:ethyl acetate=83:17 to
67:33) to obtain Compound 12 (570 mg) as a pale yellow oil.
[0895] MS (m/z): 360 [M+H].sup.+
(9)
##STR00668##
[0896] A reaction was carried out in a manner similar to the
Example 50-(6) using a mixture of Compounds 13a and 13b (250 mg)
and Compound 12 (255 mg) to obtain a mixture of Compounds 14a and
14b (199 mg) as a colorless oil.
[0897] MS (m/z): 575 [M+H].sup.+
(10)
##STR00669##
[0898] A reaction was carried out in a manner similar to the
Example 52-(7) using the mixture of Compounds 14a and 14b (199 mg)
to obtain a mixture of Compounds 15a and 15b (197 mg) as a pale
yellow oil.
[0899] MS (m/z): 561 [M+H].sup.+
(11)
##STR00670##
[0900] A reaction was carried out in a manner similar to the
Example 52-(8) using the mixture of Compounds 15a and 15b (196 mg)
to obtain Compound 16 (67 mg) of a colorless powder as a mixture of
cis/trans forms.
[0901] MS (m/z): 431 [M+H].sup.+
Example 59
[0902] (1)
##STR00671##
[0903] A mixture of Compound 1 (500 mg), Compound 2 (458 mg),
sodium methylate (821 mg) and ethanol (7 mL) was heated at reflux
for 4 days. The reaction solution was cooled and diluted with a
saturated aqueous ammonium chloride solution, and the deposit was
collected by filtration, washed with water and then dried at
45.degree. C. overnight. After drying, the solid was dissolved in
tetrahydrofuran, and dried over potassium carbonate, then
concentrated under reduced pressure to obtain Compound 3 (505 mg)
as a pale yellow solid.
[0904] MS (m/z): 300/302 [M+H].sup.+
(2)
##STR00672##
[0905] A reaction was carried out in a manner similar to the
Example 50-(5) using Compound 1 (505 mg) to obtain a mixture of
Compounds 2a and 2b (397 mg) as a pale yellow oil.
[0906] MS (m/z): 430/432 [M+H].sup.+
(3)
##STR00673##
[0907] A reaction was carried out in a manner similar to the
Example 51-(3) using Compound 3 (1011 mg) to obtain Compound 5 (952
mg) as a colorless solid.
[0908] MS (m/z): 378 [M+H].sup.+
(4)
##STR00674##
[0909] A reaction was carried out in a manner similar to the
Example 51-(4) using the mixture of Compounds 2a and 2b (300 mg) to
obtain a mixture of Compounds 6a and 6b (298 mg) as a pale yellow
oil.
[0910] MS (m/z): 601 [M+H].sup.+
(5)
##STR00675##
[0911] A reaction was carried out in a manner similar to the
Example 51-(5) using the mixture of Compounds 6a and 6b (298 mg) to
obtain Compound 7 (186 mg) as an ivory solid.
[0912] MS (m/z): 415 [M+H].sup.+
Example 60
[0913] (1)
##STR00676##
[0914] Benzotriazole (112.5 g) was dissolved in ethanol (2 L), and
a solution of cyano bromide (50 g) in acetone (200 mL) was added
dropwise under ice cooling. An aqueous solution of sodium hydroxide
(18.9 g) dissolved in water (170 mL) was then added dropwise, and
the mixture was stirred at the same temperature for 15 minutes. The
deposit was filtered, washed with cold ethanol and subsequent dried
to obtain Compound 1 (71.21 g) as a colorless solid.
[0915] MS (m/z): 264 [M+H].sup.+
(2)
##STR00677##
[0916] To a solution of Compound 1 (1000 mg) in tetrahydrofuran (20
mL) were added Compound 2 (599 mg) and triethylamine (529 .mu.L),
and the mixture was stirred at room temperature overnight. The
reaction solution was concentrated under reduced pressure, to the
residue were added methylene chloride and an aqueous potassium
carbonate solution, and the organic layer was separated, washed
with saturated brine, and concentrated under reduced pressure. To
the residue was added 20 mL of chloroform, and Compound 3 (834 mg)
and triethylamine (529 .mu.L) were added under ice cooling, and the
mixture was stirred at room temperature overnight. The reaction
solution was extracted with chloroform, and the extract was washed
with saturated brine, and dried over anhydrous sodium sulfate.
After the solution was concentrated under reduced pressure, the
obtained residue was purified by silica gel column chromatography
(n-hexane:2-propanol=97:3 to 55:45) to obtain Compound 4 (311 mg)
as a colorless solid.
[0917] MS (m/z): 448/450 [M+H].sup.+
(3)
##STR00678##
[0918] To a solution of Compound 4 (311 mg) in chloroform (6 mL)
was added hydrazine hydrate (22 .mu.L), and the mixture was stirred
at room temperature overnight. The reaction solution was
concentrated under reduced pressure, and the residue was dissolved
in N,N-dimethylformamide (6 mL), and ice-cooled. To this was added
sodium hydride (69 mg), and the mixture was stirred at room
temperature for 1 hour. The reaction solution was ice-cooled, and
(trimethylsilyl)ethoxymethyl chloride (307 .mu.L) was added
dropwise. The temperature of the reaction solution was elevated to
room temperature, and the reaction solution was stirred for 3 days.
To the reaction solution was added a saturated aqueous ammonium
chloride solution, and the mixture was extracted with ethyl
acetate. The extract was washed with saturated brine, and dried
over anhydrous sodium sulfate. After the solution was concentrated
under reduced pressure, the obtained residue was purified by silica
gel column chromatography (n-hexane:2-propanol=99:1 to 85:15) to
obtain a mixture of Compounds 5a and 5b (125 mg) as a colorless
oil.
[0919] MS (m/z): 473/475 [M+H].sup.+
(4)
##STR00679##
[0920] After the reaction was carried out in a manner similar to
the Example 50-(6) using the mixture of Compounds 5a and 5b (125
mg) and Compound 6 (150 mg), the reaction solution was filtered
through silica gel, and washed with ethyl acetate. The filtrate was
concentrated under reduced pressure, to the residue were added
trifluoroacetic acid (5 mL) and water (0.5 mL), and the mixture was
stirred at room temperature overnight. The reaction solution was
concentrated, the residue was dissolved by adding acetic acid
thereto, and the solution was concentrated again under reduced
pressure. The obtained residue was purified by LC-MS to obtain
Compound 8 (32 mg) as a beige solid.
[0921] MS (m/z): 458 [M+H].sup.+
Example 61
[0922] (1)
##STR00680##
[0923] To a solution of Compound 1 (2.00 g) in 1,4-dioxane (20 mL)
was added an aqueous sodium hydrogen carbonate solution prepared
from sodium hydrogen carbonate (781 mg) and water (15 mL), and the
mixture was stirred at room temperature for 5 minutes. To this was
added cyano bromide (985 mg), and the mixture was stirred at room
temperature for 2 hours and then at elevated temperature of
65.degree. C. for two days. The obtained crystals were collected by
filtration, sequentially washed with water and diethyl ether, and
dried to obtain Compound 2 (1.81 g) as a colorless solid.
[0924] MS (m/z): 240/242 [M+H].sup.+
(2)
##STR00681##
[0925] Compound 2 (500 mg) was dissolved in ethanol (15 mL),
potassium hydroxide (467 mg) was added, and at the temperature of
90.degree. C., and the mixture was stirred for 8 hours. After the
mixture was allowed to cool to room temperature, it was neutralized
by addition of a 2N aqueous hydrochloric acid solution. Ethyl
acetate and water were added to the reaction solution to carry out
a liquid separation. The organic layer was separated, washed with
saturated brine, passed through the phase separator and
concentrated under reduced pressure. The obtained residue was
purified by silica gel column chromatography
(chloroform:methanol=100:0 to 93:7) to obtain Compound 3 (396 mg)
as a colorless solid.
[0926] MS (m/z): 268/270 [M+H].sup.+
(3)
##STR00682##
[0927] To a solution of Compound 3 (500 mg) dissolved in
N,N-dimethylformamide (5 mL) was added 60% sodium hydride (112 mg)
under a nitrogen atmosphere under ice cooling, and the mixture was
stirred for 15 minutes. 2-(Trimethylsilyl)ethoxymethyl chloride
(491 .mu.L) was added under ice-cooling, and the mixture was
stirred for 1 hour. To the reaction solution was added a saturated
aqueous ammonium chloride solution, and the mixture was extracted
with ethyl acetate. The organic layer was washed with saturated
brine, passed through the phase separator and concentrated under
reduced pressure. The obtained residue was purified by silica gel
column chromatography (n-hexane:ethyl acetate=99:1 to 60:40) to
obtain a mixture of Compounds 4a and 4b (773 mg) as a pale yellow
powder.
[0928] MS (m/z): 398/400 [M+H].sup.+
(4)
##STR00683##
[0929] A solution of the mixture of Compounds 4a and 4b (740 mg),
palladium acetate (21 mg),
2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (76 mg), Compound 5
(747 mg) and tripotassium phosphate (789 mg) in tetrahydrofuran (10
mL) was stirred at the temperature of 50.degree. C. under a
nitrogen atmosphere overnight. After the reaction solution was
allowed to cool to room temperature, a saturated aqueous sodium
hydrogen carbonate solution was added, and the mixture was stirred.
Ethyl acetate was added to carry out a liquid separation. The
organic layer was washed with saturated brine, passed through the
phase separator and concentrated under reduced pressure. To the
obtained residue were added trifluoroacetic acid (3 mL) and water
(0.15 mL), and the mixture was stirred at room temperature
overnight. To the reaction solution was added a 2N aqueous sodium
hydroxide solution to adjust the pH to about 2 to 3, and ethyl
acetate was added to carry out a liquid separation. The organic
layer was separated, washed with saturated brine, passed through
the phase separator and concentrated under reduced pressure. The
obtained residue was purified by silica gel column chromatography
(n-hexane:ethyl acetate=80:20 to 50:50) to obtain Compound 6 (351
mg) as a pale yellow viscous material.
[0930] MS (m/z): 397 [M+H].sup.+
(5)
##STR00684##
[0931] Compound 6 (348 mg) were dissolved in tetrahydrofuran (2 mL)
and methanol (2 mL), a 2N aqueous sodium hydroxide solution (3 mL)
was added, and the mixture was stirred at 50.degree. C. for 2
hours. After the reaction solution was neutralized by addition of
2N hydrochloric acid, ethyl acetate was added to carry out a liquid
separation. The organic layer was separated, washed with saturated
brine, passed through the phase separator, and concentrated under
reduced pressure. The obtained residue was triturated with addition
of dichloromethane and a small amount of methanol, and collected by
filtration to obtain Compound 7 (186 mg) as a colorless solid.
[0932] MS (m/z): 383 [M+H].sup.+
Example 62
[0933] (1)
##STR00685##
[0934] A treatment was carried out in a manner similar to the
Example 61-(2) using Compound 1 (2.00 g) and 2-propanol (60 mL) to
obtain Compound 2 (618 mg) as a colorless solid.
[0935] MS (m/z): 282/284 [M+H].sup.+
(2)
##STR00686##
[0936] Starting from Compound 2 (610 mg), a treatment was carried
out in a manner similar to the Example 61-(3) to obtain a mixture
of Compounds 3a and 3b (476 mg) as a colorless solid.
[0937] MS (m/z): 412/414 [M+H].sup.+
(3)
##STR00687##
[0938] A solution of the mixture of Compounds 3a and 3b (473 mg),
palladium acetate (13 mg),
2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (47 mg), Compound 4
(461 mg) and tripotassium phosphate (487 mg) in tetrahydrofuran (6
mL) was stirred at the temperature of 70.degree. C. under a
nitrogen atmosphere overnight. After the reaction solution was
allowed to cool to room temperature, a saturated aqueous sodium
hydrogen carbonate solution was added to the reaction solution, and
the mixture was stirred. Ethyl acetate was added to carry out a
liquid separation. The organic layer was washed with saturated
brine, passed through the phase separator and concentrated under
reduced pressure. The obtained residue was purified by silica gel
column chromatography (n-hexane:ethyl acetate=98:2 to 65:35) to
obtain a mixture of Compounds 5a and 5b (460 mg) as a pale yellow
viscous material.
[0939] MS (m/z): 541 [M+H].sup.+
(4)
##STR00688##
[0940] To the mixture of Compounds 5a and 5b (460 mg) were added
trifluoroacetic acid (2 mL) and water (0.1 mL), and the mixture was
stirred at room temperature overnight. To the reaction solution was
added a 2N aqueous sodium hydroxide solution to adjust the pH to
about 2 to 3, and ethyl acetate was added to carry out a liquid
separation. The organic layer was separated, washed with saturated
brine, passed through the phase separator and concentrated under
reduced pressure. The obtained residue was purified by silica gel
column chromatography (n-hexane:ethyl acetate=80:20 to 50:50) to
obtain Compound 6 (144 mg) as a colorless viscous material.
[0941] MS (m/z): 411 [M+H].sup.+
(5)
##STR00689##
[0942] Starting from Compound 6 (143 mg), a treatment was carried
out in a manner similar to the Example 61-(5) to obtain Compound 7
(124 mg) as a colorless solid.
[0943] MS (m/z): 397 [M+H].sup.+
Example 63
[0944] (1)
##STR00690##
[0945] Starting from a mixture of Compounds 1a and 1b (500 mg) and
Compound 2 (526 mg), a treatment was carried out in a manner
similar to the Example 62-(3) to obtain a mixture of Compounds 3a
and 3b (355 mg) as a pale yellow viscous material.
[0946] MS (m/z): 541 [M+H].sup.+
(2)
##STR00691##
[0947] Starting from a mixture of Compounds 3a and 3b (352 mg), a
treatment was carried out in a manner similar to the Example 62-(4)
to obtain Compound 4 (43.5 mg) as a colorless viscous material.
[0948] MS (m/z): 411 [M+H].sup.+
(3)
##STR00692##
[0949] Starting from Compound 4 (43.0 mg), a treatment was carried
out in a manner similar to the Example 61-(5) to obtain Compound 5
(32.9 mg) as a white solid.
[0950] MS (m/z): 397 [M+H].sup.+
Example 64
[0951] (1)
##STR00693##
[0952] Starting from a mixture of Compounds 1a and 1b (500 mg) and
Compound 2 (526 mg), a treatment was carried out in a manner
similar to the Example 62-(3) to obtain a mixture of Compounds 3a
and 3b (708 mg) as a pale yellow viscous material.
[0953] MS (m/z): 541 [M+H].sup.+
(2)
##STR00694##
[0954] Starting from a mixture of Compounds 3a and 3b (705 mg), a
treatment was carried out in a manner similar to the Example 62-(4)
to obtain Compound 4 (480 mg) as a colorless viscous material.
[0955] MS (m/z): 411 [M+H].sup.+
(3)
##STR00695##
[0956] Starting from Compound 4 (478 mg), a treatment was carried
out in a manner similar to the Example 61-(5) to obtain Compound 5
(288 mg) as a colorless solid.
[0957] MS (m/z): 397 [M+H].sup.+
Example 65
[0958] (1)
##STR00696##
[0959] Starting from a mixture of Compounds 1a and 1b (500 mg) and
Compound 2 (526 mg), a treatment was carried out in a manner
similar to the Example 62-(3) to obtain a mixture of Compounds 3a
and 3b (723 mg) as a pale yellow viscous material.
[0960] MS (m/z): 526 [M+H].sup.+
(2)
##STR00697##
[0961] Starting from a mixture of Compounds 3a and 3b (720 mg), a
treatment was carried out in a manner similar to the Example 62-(4)
to obtain Compound 4 (463 mg) as a colorless solid.
[0962] MS (m/z): 396 [M+H].sup.+
(3)
##STR00698##
[0963] Starting from Compound 4 (463 mg), a treatment was carried
out in a manner similar to the Example 61-(5) to obtain Compound 5
(356 mg) as a colorless solid.
[0964] MS (m/z): 382 [M+H].sup.+
Example 66
[0965] (1)
##STR00699##
[0966] Starting from a mixture of Compounds 1a and 1b (1500 mg) and
Compound 2 (1035 mg), a treatment was carried out in a manner
similar to the Example 62-(3) to obtain a mixture of Compounds 3a
and 3b (1226 mg) as a white solid.
[0967] MS (m/z): 503 [M+H].sup.+
(2)
##STR00700##
[0968] To a mixture of Compounds 3a and 3b (1220 mg) were added
methanol (20 mL) and tetrahydrofuran (20 mL), 10% palladium carbon
(244 mg) was added under a hydrogen atmosphere, and the mixture was
stirred at room temperature for 6 hours. After the catalyst was
filtered off over a membrane filter, the filtrate was concentrated
under reduced pressure, and the obtained residue was purified by
silica gel column chromatography (chloroform:methanol=100:0 to
93:7) to obtain a mixture of Compounds 4a and 4b (902 mg) as a
colorless viscous material.
[0969] MS (m/z): 413 [M+H].sup.+
(3)
##STR00701##
[0970] To a solution of a mixture of Compounds 4a and 4b (500 mg)
in methylene chloride (10 mL) was added triethylamine (0.34 mL),
trifluoromethanesulfonic anhydride (0.24 mL) was added dropwise
under ice cooling, and the mixture was stirred for 1 hour. A
saturated aqueous sodium hydrogen carbonate solution was added to
carry out extraction. The organic layer was separated, washed with
saturated brine, passed through the phase separator and
concentrated under reduced pressure. The obtained residue was
purified by silica gel column chromatography (n-hexane:ethyl
acetate=90:10 to 65:35) to obtain Compounds 5a and 5b (542 mg) as a
colorless solid.
[0971] MS (m/z): 545 [M+H].sup.+
(4)
##STR00702##
[0972] Starting from a mixture of Compounds 5a and 5b (535 mg) and
Compound 6 (330 mg), a treatment was carried out in a manner
similar to the Example 62-(3) to obtain a mixture of Compounds 7a
and 7b (382 mg) as a pale yellow viscous material.
[0973] MS (m/z): 549 [M+H].sup.+
(5)
##STR00703##
[0974] Starting from a mixture of Compounds 7a and 7b (382 mg), a
treatment was carried out in a manner similar to the Example 62-(4)
to obtain Compound 8 (277 mg) as a colorless solid.
[0975] MS (m/z): 419 [M+H].sup.+
(6)
##STR00704##
[0976] To a suspension of Compound 7 (250 mg) in methanol (4 mL)
and tetrahydrofuran (4 mL) was added 10% palladium carbon (50 mg)
under a nitrogen atmosphere, and the mixture was subjected to
hydrogen substitution and stirred under a hydrogen atmosphere at
room temperature for 4 hours. The reaction solution was filtered
and concentrated under reduced pressure to obtain a mixture of
geometrical isomers of Compound 8 (219 mg) as a colorless
liquid.
[0977] MS (m/z): 421 [M+H].sup.+
(7)
##STR00705##
[0978] Starting from Compound 8 (218 mg), a treatment was carried
out in a manner similar to the Example 61-(5) to obtain a mixture
of geometrical isomers of Compound 9 (199 mg) as a colorless
solid.
[0979] MS (m/z): 407 [M+H].sup.+
Example 67
[0980] (1)
##STR00706##
[0981] To a solution of a mixture of Compounds 1a and 1b (400 mg),
Compound 2 (200 mg) and triphenylphosphine (763 mg) in
tetrahydrofuran (8 mL) were added dropwise a 40 wt % solution of
diethyl azodicarboxylate in toluene (1324 .mu.L) under ice cooling,
and the mixture was stirred at 70.degree. C. overnight. After the
mixture was allowed to cool to room temperature, the residue
obtained by concentration under reduced pressure was purified by
silica gel column chromatography (n-hexane:ethyl acetate=83:17 to
50:50) to obtain a mixture of Compounds 3a and 3b (421 mg) as a
colorless viscous material.
[0982] MS (m/z): 567 [M+H].sup.+
(2)
##STR00707##
[0983] A mixture of Compounds 3a and 3b (415 mg) was treated in a
manner similar to the Example 62-(4) to obtain Compound 4 (328 mg)
as a colorless viscous material.
[0984] MS (m/z): 437 [M+H].sup.+
(3)
##STR00708##
[0985] Compound 4 (324 mg) was treated in a manner similar to the
Example 61-(5) to obtain Compound 5 (183 mg) as a colorless
solid.
[0986] MS (m/z): 409 [M+H].sup.+
Example 68
[0987] (1)
##STR00709##
[0988] To a solution of Compound 1 (19.0 g), carbon disulfide (22.9
mL) and methyl iodide (17.7 mL) in tetrahydrofuran (380 mL) was
added sodium hydride (7.6 g) at 0.degree. C., the temperature was
brought to room temperature, and the mixture was stirred for 8
hours. Water and ethyl acetate were added and stirred to carry out
a liquid separation. The organic layer was separated, washed with
saturated brine, dried over anhydrous magnesium sulfate and
concentrated under reduced pressure. The obtained residue was
purified by silica gel column chromatography (n-hexane:ethyl
acetate=98:2 to 85:15) to obtain Compound 2 (10.8 g) as a pale
yellow solid.
[0989] MS (m/z): 304/306 [M+H].sup.+
(2)
##STR00710##
[0990] To a solution of Compound 2 (10.8 g) in methanol (50 mL) and
tetrahydrofuran (50 mL) was added dropwise hydrazine.monohydrate
(1.90 mL), and the mixture was stirred at room temperature for 1
hour. After the solvent was distilled off, to the residue was added
diethyl ether, and the mixture was stirred. The crystals was
collected by filtration and vacuum-dried to obtain Compound 3 (9.13
g) as a colorless solid.
[0991] MS (m/z): 270/272 [M+H].sup.+
(3)
##STR00711##
[0992] Compound 3 (7 g) was treated in a manner similar to the
Example 61-(3) to obtain Compound 4a (6.53 g) and Compound 4b (3.02
g) as a colorless viscous material and a colorless solid,
respectively.
[0993] MS (m/z): 400/402 [M+H].sup.+
(4)
##STR00712##
[0994] To a solution of Compound 4a (6.53 g) in methylene chloride
(80 mL) was added 3-chloroperbenzoic acid (11.2 g) at 0.degree. C.,
and the mixture was stirred at room temperature for 2 hours. A
saturated aqueous sodium hydrogen carbonate solution was added, and
the mixture was stirred and extracted with methylene chloride. The
organic layer was separated, washed with saturated brine, dried
over anhydrous magnesium sulfate and concentrated under reduced
pressure. The obtained residue was purified by silica gel column
chromatography (n-hexane:ethyl acetate=92:8 to 80:20) to obtain
Compound 5 (7.44 g) as a colorless solid.
[0995] MS (m/z): 432/434 [M+H].sup.+
(5)
##STR00713##
[0996] To a solution of sodium hydride (14.6 mg) in tetrahydrofuran
(0.5 mL) was added dropwise 2,2,2-trifluoroethanol 6 (26.1 .mu.L)
under ice cooling, and the mixture was stirred at the same
temperature for 15 minutes. To this was added a solution of
Compound 5 (79 mg) in tetrahydrofuran (1.5 mL), and the mixture was
stirred at room temperature for 2 hours. A saturated aqueous
ammonium chloride solution was added, and the mixture was stirred.
Subsequently, water and ethyl acetate were added and stirred to
carry out a liquid separation. The organic layer was separated,
washed with saturated brine, dried over anhydrous magnesium sulfate
and concentrated under reduced pressure. The obtained residue was
purified by silica gel column chromatography (n-hexane:ethyl
acetate=98:2 to 92:8) to obtain Compound 7 (77.3 mg) as a colorless
solid.
[0997] MS (m/z): 452/454 [M+H].sup.+
(6)
##STR00714##
[0998] To a solution of Compound 7 (75 mg), a
[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride
dichloromethane complex (6.8 mg) and Compound 8 (67 mg) in
N,N-dimethylformamide (1 mL) was added dropwise a 2N aqueous sodium
carbonate solution (249 .mu.L) under a nitrogen stream, and the
mixture was stirred at 60.degree. C. for 6 hours. After the mixture
was cooled to room temperature, water and ethyl acetate were added
and stirred to carry out a liquid separation. The organic layer was
separated, washed with saturated brine, passed through the phase
separator, and concentrated under reduced pressure. The obtained
residue was purified by silica gel column chromatography
(n-hexane:ethyl acetate=95:5 to 85:15) to obtain Compound 9 (74.3
mg) as a colorless viscous material.
[0999] MS (m/z): 581 [M+H].sup.+
(7)
##STR00715##
[1000] To Compound 9 (73 mg) were added trifluoroacetic acid (1 mL)
and water (0.05 mL), and the mixture was stirred at room
temperature for 6 hours. A 2N aqueous sodium hydroxide solution was
added to adjust the pH to about 2-3, and an extraction with ethyl
acetate was carried out. The organic layer was separated, washed
with saturated brine, passed through the phase separator, and
concentrated under reduced pressure. To the obtained residue were
added methanol (0.5 mL), tetrahydrofuran (0.5 mL) and a 2N aqueous
sodium hydroxide solution (0.5 mL), and the mixture was stirred at
50.degree. C. for 2 hours. After the mixture was neutralized with
addition of ethyl acetate and a 1N aqueous hydrochloric acid
solution, an extraction was carried out. The organic layer was
separated, washed with saturated brine, passed through the phase
separator, and concentrated under reduced pressure. To the obtained
residue was added diethyl ether, and the mixture was stirred. The
obtained crystals were collected by filtration and vacuum-dried to
obtain Compound 10 (34 mg) as a colorless solid.
[1001] MS (m/z): 437 [M+H].sup.+
Example 69
[1002] (1)
##STR00716##
[1003] Starting from Compound 1 (5.00 g) and Compound 2 (4.65 g), a
treatment was carried out in a manner similar to the Example 68-(6)
to obtain Compound 3 (4.45 g) as a pale yellow powder.
[1004] MS (m/z): 561 [M+H].sup.+
(2)
##STR00717##
[1005] A suspension of Compound 3 (48 mg), Compound 4 (19.2 mg) and
sodium carbonate (59 mg) in N-methylpyrrolidone (0.5 mL) was
stirred at 120.degree. C. for 1 hour. After the mixture was cooled
to room temperature, water and ethyl acetate were added and stirred
to carry out a liquid separation. The organic layer was separated,
washed with saturated brine, passed through the phase separator and
concentrated under reduced pressure. The obtained residue was
purified by silica gel column chromatography (n-hexane:ethyl
acetate=88:12 to 70:30) to obtain Compound 5 (40 mg) as a colorless
viscous material.
[1006] MS (m/z): 593 [M+H].sup.+
(3)
##STR00718##
[1007] Starting from Compound 5 (21.0 mg), a treatment was carried
out in a manner similar to the Example 68-(7) to obtain Compound 6
(11.8 mg) as a colorless solid.
[1008] MS (m/z): 449 [M+H].sup.+
(4)
##STR00719##
[1009] To a suspension of Compound 6 (266 mg) in acetonitrile (2
mL) was added dropwise a 1N aqueous sodium hydroxide solution (593
.mu.L), and the mixture was stirred at room temperature for 8
hours. After the solvent was distilled off under reduced pressure,
the residue crystals were triturated with diethyl ether, collected
by filtration and vacuum-dried to obtain Compound 7 (253 mg) as a
colorless solid.
[1010] MS (m/z): 447 [M-Na].sup.-
Example 70
[1011] (1)
##STR00720##
[1012] Starting from Compound 1 (400 mg) and Compound 2 (186 mg), a
treatment was carried out in a manner similar to the Example 69-(2)
to obtain Compound 3 (363 mg) as a colorless viscous material.
[1013] MS (m/z): 611 [M+H].sup.+
(2)
##STR00721##
[1014] Starting from Compound 3 (360 mg), a treatment was carried
out in a manner similar to the Example 68-(7) to obtain Compound 4
(205 mg) as a colorless solid.
[1015] MS (m/z): 467 [M+H].sup.+
Example 71
[1016] (1)
##STR00722##
[1017] Starting from Compound 1 (400 mg) and Compound 2 (186 mg), a
treatment was carried out in a manner similar to the Example 69-(2)
to obtain Compound 3 (403 mg) as a colorless viscous material.
[1018] MS (m/z): 611 [M+H].sup.+
(2)
##STR00723##
[1019] Starting from Compound 3 (400 mg), a treatment was carried
out in a manner similar to the Example 68-(7) to obtain Compound 4
(220 mg) as a colorless solid.
[1020] MS (m/z): 467 [M+H].sup.+
Example 72
[1021] (1)
##STR00724##
[1022] Starting from Compound 1 (100 mg) and Compound 2 (33.9 mg),
a treatment was carried out in a manner similar to the Example
69-(2) to obtain Compound 3 (83 mg) as a colorless viscous
material.
[1023] MS (m/z): 576 [M+H].sup.+
(2)
##STR00725##
[1024] Starting from Compound 3 (82 mg), a treatment was carried
out in a manner similar to the Example 68-(7) to obtain Compound 4
(52 mg) as a colorless solid.
[1025] MS (m/z): 432 [M+H].sup.+
Example 73
[1026] (1)
##STR00726##
[1027] Starting from Compound 1 (400 mg) and Compound 2 (163 mg), a
treatment was carried out in a manner similar to the Example 68-(5)
to obtain Compound 3 (262 mg) as a colorless viscous material.
[1028] MS (m/z): 595 [M+H].sup.+
(2)
##STR00727##
[1029] Starting from Compound 3 (260 mg), a treatment was carried
out in a manner similar to the Example 68-(7) to obtain Compound 4
(157 mg) as a colorless solid.
[1030] MS (m/z): 451 [M+H].sup.+
Example 74
[1031] (1)
##STR00728##
[1032] Starting from Compound 1 (400 mg) and Compound 2 (214 mg), a
treatment was carried out in a manner similar to the Example 68-(5)
to obtain Compound 3 (406 mg) as a colorless solid.
[1033] MS (m/z): 631 [M+H].sup.+
(2)
##STR00729##
[1034] To the carboxylic acid compound synthesized from Compound 3
(402 mg) by treating it in a manner similar to the Example 68-(7)
were added 1 mL of acetonitrile and an equal amount of a 1 N
aqueous sodium hydroxide solution, and additionally diethyl ether
was added until complete dissolution. After the solvent was
distilled off under reduced pressure, the residue was stirred in a
small amount of ethyl acetate and diethyl ether, and the crystals
were collected by filtration and dried under reduced pressure to
obtain Compound 4 (271 mg) as a colorless solid.
[1035] MS (m/z): 485 [M-Na].sup.-
Example 75
[1036] (1)
##STR00730##
[1037] Starting from Compound 1 (300 mg) and Compound 2 (128 mg), a
treatment was carried out in a manner similar to the Example 69-(2)
to obtain Compound 3 (144 mg) as a colorless viscous material.
[1038] MS (m/z): 600 [M+H].sup.+
(2)
##STR00731##
[1039] Starting from Compound 3 (142 mg), a treatment was carried
out in a manner similar to the Example 68-(7) to obtain Compound 4
(57 mg) as a colorless solid.
[1040] MS (m/z): 456 [M+H].sup.+
Example 76
[1041] (1)
##STR00732##
[1042] Starting from Compound 1 (100 mg) and Compound 2 (33.9 mg),
a treatment was carried out in a manner similar to the Example
69-(2) to obtain Compound 3 (13.9 mg) as a colorless solid.
[1043] MS (m/z): 576 [M+H].sup.+
(2)
##STR00733##
[1044] Starting from Compound 3 (30 mg), a treatment was carried
out in a manner similar to the Example 68-(7) to obtain Compound 4
(18.7 mg) as a colorless solid.
[1045] MS (m/z): 432 [M+H].sup.+
Example 77
[1046] (1)
##STR00734##
[1047] From Compound 1 (200 mg) and Compound 2 (77.8 mg), a
treatment was carried out in a manner similar to the Example 69-(2)
to obtain Compound 3 (38 mg) as a colorless solid.
[1048] MS (m/z): 590 [M+H].sup.+
(2)
##STR00735##
[1049] Starting from Compound 3 (36 mg), a treatment was carried
out in a manner similar to the Example 68-(7) to obtain Compound 4
(24.8 mg) as a colorless solid.
[1050] MS (m/z): 446 [M+H].sup.+
Example 78
[1051] (1)
##STR00736##
[1052] To a solution of Compound 1 (3.00 g) and potassium carbonate
(311 mg) in dimethylsulfoxide (45 mL) was added an aqueous 30%
hydrogen peroxide solution (1.7 mL) under ice cooling, and the
mixture was stirred at room temperature overnight. To this was
added an additional aqueous 30% hydrogen peroxide solution (0.5
mL), and the mixture was further stirred at room temperature for 4
days. Water was slowly added dropwise, and the obtained crystals
were collected by filtration, washed with diethyl ether and
subsequently vacuum-dried to obtain Compound 2 (1284 mg) as a
colorless solid.
[1053] MS (m/z): 218/220 [M+H].sup.+
(2)
##STR00737##
[1054] Starting from Compound 2 (1200 mg), a treatment was carried
out in a manner similar to the Example 68-(1) to obtain Compound 3
(621 mg) as a pale yellow solid.
[1055] MS (m/z): 322/324 [M+H].sup.+
(3)
##STR00738##
[1056] Starting from Compound 3 (640 mg), a treatment was carried
out in a manner similar to the Example 68-(2) to obtain Compound 4
(479 mg) as a colorless solid.
[1057] MS (m/z): 288/290 [M+H].sup.+
(4)
##STR00739##
[1058] Starting from Compound 4 (445 mg), a treatment was carried
out in a manner similar to the Example 61-(3) to obtain Compound 5a
(328 mg) and Compound 5b (351 mg) both as colorless viscous
materials.
[1059] Compound 5a: MS (m/z): 418/420 [M+H].sup.+
[1060] Compound 5b: MS (m/z): 418/420 [M+H].sup.+
(5)
##STR00740##
[1061] Starting from Compound 5a (325 mg), a treatment was carried
out in a manner similar to the Example 68-(4) to obtain Compound 6a
(331 mg) as a colorless viscous material.
[1062] MS (m/z): 450/452 [M+H].sup.+
(6)
##STR00741##
[1063] Starting from Compound 6a (330 mg) and Compound 7 (112
.mu.L), a treatment was carried out in a manner similar to the
Example 68-(5) to obtain Compound 8a (265 mg) as a colorless
viscous material.
[1064] MS (m/z): 430/432 [M+H].sup.+
(7)
##STR00742##
[1065] Starting from Compound 8a (260 mg) and Compound 9 (253 mg),
a treatment was carried out in a manner similar to the Example
68-(6) to obtain Compound 10a (333 mg) as a colorless viscous
material.
[1066] MS (m/z): 573 [M+H].sup.+
(8)
##STR00743##
[1067] Starting from Compound 10a (330 mg), a treatment was carried
out in a manner similar to the Example 62-(4) to obtain Compound 11
(167 mg) as a colorless viscous material.
[1068] MS (m/z): 443 [M+H].sup.+
(9)
##STR00744##
[1069] Starting from Compound 11 (166 mg), a treatment was carried
out in a manner similar to the Example 61-(5) to obtain Compound 12
(132 mg) as a colorless solid.
[1070] MS (m/z): 429 [M+H].sup.+
Example 79
[1071] (1)
##STR00745##
[1072] Starting from Compound 1 (3000 mg), a treatment was carried
out in a manner similar to the Example 78-(1) to obtain Compound 2
(2842 mg) as a colorless solid.
[1073] MS (m/z): 201/203 [M+H].sup.+
(2)
##STR00746##
[1074] Starting from Compound 2 (2800 mg), a treatment was carried
out in a manner similar to the Example 68-(1) to obtain Compound 3
(257 mg) as a pale yellowish-orange solid.
[1075] MS (m/z): 305/307 [M+H].sup.+
(3)
##STR00747##
[1076] Starting from Compound 3 (255 mg), a treatment was carried
out in a manner similar to the Example 68-(2) to obtain Compound 4
(166 mg) a pale yellow solid.
[1077] MS (m/z): 271/273 [M+H].sup.+
(4)
##STR00748##
[1078] Starting from Compound 5 (162 mg), a treatment was carried
out in a manner similar to the Example 61-(3) to obtain Compound 6a
(92.9 mg) as a colorless viscous material and Compound 6b (89.1 mg)
as a pale yellow solid, respectively.
[1079] Compound 6a: MS (m/z): 401/403 [M+H].sup.+
[1080] Compound 6b: MS (m/z): 401/403 [M+H].sup.+
(5)
##STR00749##
[1081] To a solution of Compound 6b (88.0 mg) in methylene chloride
(1 mL) was added acetic acid (50 .mu.L), 3-chloroperbenzoic acid
(151 mg) was added under ice cooling, and the mixture was stirred
at room temperature for 3 hours. A saturated aqueous sodium
hydrogen carbonate solution was added, and the mixture was stirred
and extracted with methylene chloride. The organic layer was
separated, washed with saturated brine, dried over anhydrous
magnesium sulfate, and concentrated under reduced pressure. The
obtained residue was purified by silica gel column chromatography
(n-hexane:ethyl acetate=85:15 to 66:34) to obtain Compound 7b (53.2
mg) as a pale yellowish-orange solid.
[1082] MS (m/z): 433/435 [M+H].sup.+
(6)
##STR00750##
[1083] Starting from Compound 7b (53.0 mg) and Compound 8 (19
.mu.L), a treatment was carried out in a manner similar to the
Example 68-(5) to obtain Compound 9b (27.0 mg) as a colorless
viscous material.
[1084] MS (m/z): 413/415 [M+H].sup.+
(7)
##STR00751##
[1085] Starting from Compound 9b (26.0 mg) and Compound 10 (43.9
mg), a treatment was carried out in a manner similar to the Example
68-(6) to obtain Compound 11b (31.6 mg) as a colorless viscous
material.
[1086] MS (m/z): 556 [M+H].sup.+
(8)
##STR00752##
[1087] Starting from Compound 11b (31.0 mg), a treatment was
carried out in a manner similar to the Example 68-(7) to obtain
Compound 12 (13.8 mg) as a colorless solid.
[1088] MS (m/z): 412 [M+H].sup.+
Example 80
[1089] (1)
##STR00753##
[1090] Starting from Compound 1 (2000 mg), a treatment was carried
out in a manner similar to the Example 68-(1) to obtain Compound 2
(1153 mg) as a white solid.
[1091] MS (m/z): 261/263 [M+H].sup.+
(2)
##STR00754##
[1092] Starting from Compound 2 (1150 mg), a treatment was carried
out in a manner similar to the Example 68-(2) to obtain Compound 3
(829 mg) as a colorless solid.
[1093] MS (m/z): 227/229 [M+H].sup.+
(3)
##STR00755##
[1094] Starting from Compound 3 (500 mg), a treatment was carried
out in a manner similar to the Example 61-(3) to obtain Compound 4a
(478 mg) and Compound 4b (215 mg) both as colorless viscous
materials.
[1095] Compound 4a: MS (m/z): 357/359 [M+H].sup.+
[1096] Compound 4b: MS (m/z): 357/359 [M+H].sup.+
(4)
##STR00756##
[1097] Starting from Compound 4a (470 mg), a treatment was carried
out in a manner similar to the Example 79-(5) to obtain Compound 5a
(363 mg) as a colorless viscous material.
[1098] MS (m/z): 389/391 [M+H].sup.+
(5)
##STR00757##
[1099] Starting from Compound 5a (360 mg) and Compound 6 (141
.mu.L), a treatment was carried out in a manner similar to the
Example 68-(5) to obtain Compound 7a (272 mg) as a colorless
solid.
[1100] MS (m/z): 369/371 [M+H].sup.+
(6)
##STR00758##
[1101] Starting from Compound 7a (200 mg) and Compound 8 (454 mg),
a treatment was carried out in a manner similar to the Example
68-(6) to obtain Compound 9a (258 mg) as a colorless viscous
material.
[1102] MS (m/z): 556 [M+H].sup.+
(7)
##STR00759##
[1103] Starting from Compound 9a (254 mg), a treatment was carried
out in a manner similar to the Example 68-(7) to obtain Compound 10
(156 mg) as a colorless solid.
[1104] MS (m/z): 412 [M+H].sup.+
Example 81
[1105] (1)
##STR00760##
[1106] A reaction was carried out in a manner similar to the
Example 68-(6) using Compound 2 (400 mg) and a mixture of Compounds
1a and 1b (363 mg) to obtain a mixture of Compounds 3a and 3b (379
mg) as a colorless viscous material.
[1107] MS (m/z): 565 [M+H].sup.+
(2)
##STR00761##
[1108] A reaction was carried out in a manner similar to the
Example 52-(7) using the mixture of Compounds 3a and 3b (375 mg) to
obtain a mixture of Compounds 4a and 4b (366 mg) as a colorless
viscous material.
[1109] MS (m/z): 551 [M+H].sup.+
(3)
##STR00762##
[1110] A reaction was carried out in a manner similar to the
Example 52-(8) using the mixture of Compounds 4a and 4b (363 mg) to
obtain Compound 5 (218 mg) as a colorless solid.
[1111] MS (m/z): 421 [M+H].sup.+
Example 82
[1112] (1)
##STR00763##
[1113] Starting from Compound 1 (500 mg), a treatment was carried
out in a manner similar to the Example 68-(5) to obtain Compound 3
(343 mg) as a colorless solid.
[1114] MS (m/z): 470/472 [M+H].sup.+
(2)
##STR00764##
[1115] Starting from Compound 3 (341 mg) and Compound 4 (304 mg), a
treatment was carried out in a manner similar to the Example 68-(6)
to obtain Compound 5 (436 mg) as a colorless viscous material.
[1116] MS (m/z): 613 [M+H].sup.+
(3)
##STR00765##
[1117] Starting from Compound 5 (435 mg), a treatment was carried
out in a manner similar to the Example 68-(7) to obtain Compound 6
(290 mg) as a colorless solid.
[1118] MS (m/z): 469 [M+H].sup.+
Example 83
[1119] (1)
##STR00766##
[1120] Starting from Compound 1 (500 mg), a treatment was carried
out in a manner similar to the Example 69-(2) to obtain Compound 3
(357 mg) as a colorless viscous material.
[1121] MS (m/z): 482/484 [M+H].sup.+
(2)
##STR00767##
[1122] Starting from Compound 3 (355 mg) and Compound 4 (308 mg), a
treatment was carried out in a manner similar to Example 68-(6) to
obtain Compound 5 (464 mg) as a colorless viscous material.
[1123] MS (m/z): 625 [M+H].sup.+
(3)
##STR00768##
[1124] Starting from Compound 5 (450 mg), a treatment was carried
out in a manner similar to Example 68-(7) to obtain Compound 6 (293
mg) as a colorless solid.
[1125] MS (m/z): 481 [M+H].sup.+
Example 84
[1126] (1)
##STR00769##
[1127] Under ice cooling, to a solution of Compound 1 (2 g) in
tetrahydrofuran (10 mL) was added dropwise a 1.6M lithium
bis(trimethylsilyl)amide/tetrahydrofuran solution (7.5 mL), and the
mixture was stirred at room temperature for 3 hours. The reaction
solution was ice cooled, and 4N hydrogen chloride-1,4-dioxane (6.2
mL) was added. Diethyl ether was added, and the deposit was
collected by filtration. The filtrate was concentrated under
reduced pressure, and the deposit was washed with diethyl ether and
collected by filtration. The obtained deposits were combined to be
used for the next reaction. A solution of Compound 3 (0.75 mL) and
hydrazine hydrate (0.29 mL) in tetrahydrofuran (8 mL) was stirred
at 65.degree. C. for 1 hour. The reaction solution was cooled to
room temperature, the deposit obtained above was added, and the
mixture was stirred at 65.degree. C. for 2 hours. To the reaction
solution was added water, and the mixture was extracted with ethyl
acetate. The extract was washed with saturated brine, dried over
anhydrous magnesium sulfate, and concentrated under reduced
pressure. The obtained residue was purified by silica gel column
chromatography (n-hexane:ethyl acetate=100:0 to 80:20) to obtain
Compound 5 (165 mg) as a colorless solid.
[1128] MS (m/z): 310/312 [M+H].sup.+
(2)
##STR00770##
[1129] A reaction was carried out in a manner similar to the
Example 50-(5) using Compound 5 (164 mg) to obtain a mixture of
Compounds 6a and 6b (228 mg) as a colorless viscous material.
[1130] MS (m/z): 440/442 [M+H].sup.+
(3)
##STR00771##
[1131] A reaction was carried out in a manner similar to the
Example 50-(6) using the mixture of Compounds 6a and 6b (220 mg),
and Compound 7 (174 mg) to obtain a mixture of Compounds 8a and 8b
(263 mg) as a colorless viscous material.
[1132] MS (m/z): 583 [M+H].sup.+
(4)
##STR00772##
[1133] A reaction was carried out in a manner similar to the
Example 52-(7) using the mixture of Compounds 8a and 8b (260 mg) to
obtain a mixture of Compounds 9a and 9b (259 mg) as a colorless
viscous material.
[1134] MS (m/z): 569 [M+H].sup.+
(5)
##STR00773##
[1135] A reaction was carried out in a manner similar to the
Example 52-(8) using Compounds 9a and 9b (254 mg) to obtain
Compound 10 (130 mg) as a colorless solid.
[1136] MS (m/z): 439 [M+H].sup.+
Example 85
[1137] (1)
##STR00774##
[1138] To a solution of Compound 1 (10 g) in methylene chloride
(200 mL) were added oxalyl chloride (4.43 mL) and
N,N-dimethylformamide (0.16 mL) at room temperature, and the
mixture was stirred at room temperature for 2 hours. The reaction
solution was concentrated under reduced pressure, the residue was
dissolved in tetrahydrofuran (50 mL), and this was added dropwise
to a suspension of thiosemicarbazide (3.85 g) and pyridine (75 mL)
under ice cooling over 10 minutes. After dropwise addition, the
mixture was stirred at room temperature for 2 hours and
concentrated under reduced pressure. The residue was dissolved in a
2N aqueous sodium hydroxide solution (210 mL), and heated at reflux
for 16 hours. The reaction solution was ice cooled and neutralized
with concentrated hydrochloric acid (35 mL). The deposit was
collected by filtration and washed with water and methanol. The
obtained solid was suspended and washed in diethyl ether (50 mL),
collected by filtration and dried at 50.degree. C. under reduced
pressure to obtain Compound 2 (9.46 g) as a beige solid.
[1139] MS (m/z): 291/293/295 [M+H].sup.+
(2)
##STR00775##
[1140] Compound 2 (9.44 g) was suspended in ethanol (24 mL), and a
2N aqueous sodium hydroxide solution (17.8 mL) and methyl iodide
(2.2 mL) were added at room temperature. After the reaction
solution was stirred at room temperature for 30 minutes, the
deposit was collected by filtration, washed with ethanol and
vacuum-dried at 50.degree. C. to obtain Compound 3 (7.815 g) as a
beige solid.
[1141] MS (m/z): 305/307/309 [M+H].sup.+
(3)
##STR00776##
[1142] A reaction was carried out in a manner similar to the
Example 61-(3) using Compound 3 (7.815 g) to obtain Compound 4a
(7.335 g) and Compound 4b (4.294 g) as yellow viscous materials
respectively.
[1143] MS (m/z): 435/437/439 [M+H].sup.+
(4)
##STR00777##
[1144] A reaction was carried out in a manner similar to the
Example 68-(4) using Compound 4b (3.69 g) to obtain Compound 5
(3.323 g) as a colorless solid.
[1145] MS (m/z): 466/468/470 [M+H].sup.+
(5)
##STR00778##
[1146] A reaction was carried out in a manner similar to the
Example 68-(5) using Compound 5 (1 g) to obtain Compound 6 (826 mg)
as a colorless viscous material.
[1147] MS (m/z): 447/449/451 [M+H].sup.+
(6)
##STR00779##
[1148] A reaction was carried out in a manner similar to the
Example 68-(6) using Compound 6 (400 mg) to obtain Compound 8 (429
mg) as a colorless viscous material.
[1149] MS (m/z): 590/592 [M+H].sup.+
(7)
##STR00780##
[1150] A reaction was carried out in a manner similar to the
Example 68-(7) using Compound 8 (242 mg) to obtain Compound 9 (210
mg) as a colorless solid.
[1151] MS (m/z): 576/578 [M+H].sup.+
(8)
##STR00781##
[1152] To a solution of Compound 9 (205 mg) in tetrahydrofuran (4
mL) was added a 1M solution of tetrabutylammonium fluoride in
tetrahydrofuran (1.78 mL), and the mixture was stirred at
70.degree. C. for 23 hours. A saturated aqueous ammonia chloride
solution was added, and the mixture was extracted with ethyl
acetate. The organic layer was washed with saturated brine, dried
over anhydrous magnesium sulfate and concentrated under reduced
pressure. The obtained residue was purified by silica gel column
chromatography (chloroform:methanol=100/0 to 90/10) to obtain a
mixture of Compounds 9 and 10. To this were added 2 mL of
trifluoroacetic acid and 0.2 mL of water, and the mixture was
stirred at room temperature for 2 hours. After the reaction
solution was ice cooled and neutralized with a 1N aqueous sodium
hydroxide solution, its pH was adjusted to 4 with 1N hydrochloric
acid, and then it was extracted with ethyl acetate. The organic
layer was washed with saturated brine, dried over anhydrous
magnesium sulfate and concentrated under reduced pressure. The
obtained residue was purified by silica gel column chromatography
(chloroform:methanol=100/0 to 90/10) to obtain Compound 10 (109 mg)
as a colorless solid.
[1153] MS (m/z): 446/448 [M+H].sup.+
Example 86
[1154] (1)
##STR00782##
[1155] Starting from Compound 1 (4400 mg), a treatment was carried
out in a manner similar to the Example 68-(6) to obtain Compound 3
(4750 mg) as a pale yellow solid.
[1156] MS (m/z): 386 [M+H].sup.+
(2)
##STR00783##
[1157] To a solution of Compound 3 (4740 mg) in methylene chloride
(20 mL) was added trifluoroacetic acid (20 mL), and the mixture was
stirred at room temperature for 4 hours. The solvent was distilled
off under reduced pressure, and azeotroped with toluene. To the
residue was added diethyl ether, and the mixture was stirred. The
obtained crystals were collected by filtration and subsequently
vacuum-dried to obtain Compound 4 (3144 mg) as a colorless
solid.
[1158] MS (m/z): 330 [M+H].sup.+
(3)
##STR00784##
[1159] To a solution of Compound 4 (200 mg) in methylene chloride
(8 mL) was added N,N-dimethylformamide (7 .mu.L), thionyl chloride
(266 .mu.L) was added dropwise, and the mixture was stirred at room
temperature for 2 hours. The solvent was distilled off under
reduced pressure, and azeotroped to dry with toluene. To the
residue were added toluene (8 mL) and potassium thiocyanate (354
mg), and the mixture was stirred at room temperature for 1 hour.
After the supernatant (4 mL) was removed, to the solution
containing the residual insoluble salt was added methanol (0.4 mL),
the temperature was brought to 70.degree. C., and the mixture was
stirred for 2 hours. After the reaction solution was cooled to room
temperature, to this was added hydrazine.monohydrate (59 .mu.L),
and the mixture was stirred at room temperature for 1 hour. Ethyl
acetate and saturated brine were added, and the mixture was stirred
to carry out a separation. The organic layer was passed through the
phase separator and subsequently concentrated under reduced
pressure. The obtained residue was purified by silica gel column
chromatography (n-hexane:ethyl acetate=70:30 to 40:60) to obtain
Compound 5 (29.4 mg) as a white solid.
[1160] MS (m/z): 383 [M+H].sup.+
(4)
##STR00785##
[1161] Starting from Compound 5 (29.0 mg), a treatment was carried
out in a manner similar to the Example 61-(5) to obtain Compound 6
(21.8 mg) as a colorless solid.
[1162] MS (m/z): 369 [M+H].sup.+
Example 87
[1163] (1)
##STR00786##
[1164] Starting from Compound 1 (300 mg) and Compound 2 (309 mg), a
treatment was carried out in a manner similar to the Example 68-(6)
to obtain Compound 3 (294 mg) as a colorless viscous material.
[1165] MS (m/z): 627 [M+H].sup.+
(2)
##STR00787##
[1166] To Compound 3 (293 mg) were added trifluoroacetic acid (1
mL) and water (0.05 mL), and the mixture was stirred at room
temperature for 3 hours. The reaction solution was neutralized by
addition of a 2N aqueous sodium hydroxide solution, and stirred at
room temperature for 1 hour. Subsequently, ethyl acetate was added
to carry out a liquid separation. The organic layer was separated,
washed with saturated brine, passed through the phase separator and
concentrated under reduced pressure. The obtained residue was
purified by silica gel column chromatography (n-hexane:ethyl
acetate=60:40 to 20:80). The solvent of the fraction including the
target compound was distilled off under reduced pressure, to the
residue were added diisopropyl ether and a small amount of ethyl
acetate, and the obtained crystals were collected by filtration and
vacuum-dried to obtain Compound 4 (147 mg) as a colorless
solid.
[1167] MS (m/z): 441 [M+H].sup.+
Example 88
[1168] (1)
##STR00788##
[1169] To a solution of Compound 1 (10.0 g) in tetrahydrofuran (50
mL) was added N, N-dimethylformamide (0.5 mL) and thionyl chloride
(12.4 mL) was added dropwise, and the mixture was stirred at
50.degree. C. for 2 hours. After the solvent was distilled off
under reduced pressure, the residue was dissolved in
tetrahydrofuran (25 mL), and the solution was added slowly dropwise
to a suspension of Compound 2 (3.87 g) in pyridine (50 mL) under
ice cooling. The mixture was stirred at the same temperature for 30
minutes and at room temperature for 3 hours. After the solvent was
distilled off under reduced pressure, water (50 mL) and a 2N
aqueous sodium hydroxide solution (200 mL) were added, and the
mixture was stirred at 110.degree. C. for 3 hours. The mixture was
neutralized by slow addition of concentrated hydrochloric acid
(about 40 mL) under ice cooling, and the obtained crystals were
collected by filtration. The crystals were washed with diethyl
ether and vacuum-dried to obtain Compound 3 (8.36 g) as a pale
yellow solid.
[1170] MS (m/z): 290/292 [M+H].sup.+
(2)
##STR00789##
[1171] To a suspension of Compound 3 (8.20 g) in ethanol (19 mL)
was added dropwise a 2N aqueous sodium hydroxide solution (15.5 mL)
and methyl iodide (1.93 mL) was further added, and the mixture was
stirred at room temperature for 5 minutes. The obtained crystals
were collected by filtration, washed with water and diethyl ether,
and subsequently dried to obtain Compound 4 (3.95 g) as a pale
yellowish brown solid.
[1172] MS (m/z): 304/306 [M+H].sup.+
(3)
##STR00790##
[1173] Starting from Compound 4 (3940 mg), a treatment was carried
out in a manner similar to the Example 61-(3) to obtain Compound 5a
(1353 mg) and Compound 5b (1020 mg) as colorless viscous materials
respectively.
[1174] Compound 5a: MS (m/z): 434/436 [M+H].sup.+
[1175] Compound 5b: MS (m/z): 434/436 [M+H].sup.+
(4)
##STR00791##
[1176] Starting from Compound 5a (1330 mg), a treatment was carried
out in a manner similar to the Example 68-(4) to obtain Compound 6a
(1221 mg) as a pale yellow viscous material.
[1177] MS (m/z): 466/468 [M+H].sup.+
(5)
##STR00792##
[1178] Starting from Compound 6a (800 mg) and Compound 7 (261
.mu.L), a treatment was carried out in a manner similar to the
Example 68-(5) to obtain Compound 8a (481 mg) as a colorless
viscous material.
[1179] MS (m/z): 446/448 [M+H].sup.+
(6)
##STR00793##
[1180] Starting from Compound 8a (479 mg) and Compound 9 (393 mg),
a treatment was carried out in a manner similar to the Example
68-(6) to obtain Compound 10a (538 mg) as a colorless viscous
material.
[1181] MS (m/z): 589/591 [M+H].sup.+
(7)
##STR00794##
[1182] To Compound 10a (300 mg) in tetrahydrofuran (4 mL) was added
dropwise a 1M tetrabutylammonium fluoride in tetrahydrofuran (2.5
mL), and the mixture was stirred at 70.degree. C. for 4 days. After
neutralization by addition of 1N aqueous hydrochloric acid
solution, an extraction with ethyl acetate was carried out. The
organic layer was washed with saturated brine, passed through the
phase separator and concentrated under reduced pressure. The
obtained residue was purified by silica gel column chromatography
(n-hexane:ethyl acetate=65:35 to 5:95) to obtain Compound 11 (136
mg) as a colorless solid.
[1183] MS (m/z): 445/447 [M+H].sup.+
Example 89
[1184] (1)
##STR00795##
[1185] Starting from Compound 1 (400 mg) and Compound 2 (209 mg), a
treatment was carried out in a manner similar to the Example 68-(5)
to obtain Compound 3 (368 mg) as a pale yellow viscous
material.
[1186] MS (m/z): 646 [M+H].sup.+
(2)
##STR00796##
[1187] Starting from Compound 3 (366 mg), a treatment was carried
out in a manner similar to the Example 68-(7) to obtain Compound 4
(218 mg) as a colorless solid.
[1188] MS (m/z): 502 [M+H].sup.+
Example 90
[1189] (1)
##STR00797##
[1190] Starting from Compound 1 (300 mg), a treatment was carried
out in a manner similar to the Example 69-(2) to obtain Compound 3
(257 mg) as a colorless viscous material.
[1191] MS (m/z): 608 [M+H].sup.+
(2)
##STR00798##
[1192] Starting from Compound 3 (255 mg), a treatment was carried
out in a manner similar to the Example 68-(7) to obtain Compound 4
(150 mg) as a colorless solid.
[1193] MS (m/z): 464 [M+H].sup.+
Example 91
[1194] (1)
##STR00799##
[1195] Starting from Compound 1 (260 mg) and Compound 2 (304 mg), a
treatment was carried out in a manner similar to the Example 68-(6)
to obtain Compound 3 (279 mg) as a pale yellow viscous
material.
[1196] MS (m/z): 610 [M+H].sup.+
(2)
##STR00800##
[1197] Starting from Compound 3 (278 mg), a treatment was carried
out in a manner similar to the Example 87-(2) to obtain Compound 4
(83.4 mg) as a colorless solid.
[1198] MS (m/z): 424 [M+H].sup.+
Example 92
[1199] (1)
##STR00801##
[1200] Starting from Compound 1 (330 mg) and Compound 2 (473 mg), a
treatment was carried out in a manner similar to the Example 68-(6)
to obtain Compound 3 (511 mg) as a pale brown viscous material.
[1201] MS (m/z): 630 [M+H].sup.++
(2)
##STR00802##
[1202] Starting from Compound 3 (508 mg), a treatment was carried
out in a manner similar to the Example 88-(7) to obtain Compound 4
(217 mg) as a colorless solid.
[1203] MS (m/z): 410 [M+H].sup.+
Example 93
[1204] (1)
##STR00803##
[1205] Starting from Compound 1 (380 mg) and Compound 2 (523 mg), a
treatment was carried out in a manner similar to the Example 68-(6)
to obtain Compound 3 (432 mg) as a colorless viscous material.
[1206] MS (m/z): 647 [M+H].sup.+
(2)
##STR00804##
[1207] Starting from Compound 3 (428 mg), a treatment was carried
out in a manner similar to the Example 88-(7) to obtain Compound 4
(204 mg) as a colorless solid.
[1208] MS (m/z): 427 [M+H].sup.+
Example 94
[1209] (1)
##STR00805##
[1210] Starting from Compound 1 (200 mg) and Compound 2 (104 mg), a
treatment was carried out in a manner similar to the Example 68-(5)
to obtain Compound 3 (85.2 mg) as a colorless viscous material.
[1211] MS (m/z): 584 [M+H].sup.+
(2)
##STR00806##
[1212] Starting from Compound 3 (85.0 mg), a treatment was carried
out in a manner similar to the Example 88-(7) to obtain Compound 4
(36.5 mg) as a colorless solid.
[1213] MS (m/z): 440 [M+H].sup.+
Example 95
[1214] (1)
##STR00807##
[1215] Starting from Compound 1 (400 mg) and Compound 2 (99 .mu.L),
a treatment was carried out in a manner similar to the Example
68-(5) to obtain Compound 3 (385 mg) as a pale yellow viscous
material.
[1216] MS (m/z): 596 [M+H].sup.+
(2)
##STR00808##
[1217] Starting from Compound 3 (338 mg), a treatment was carried
out in a manner similar to the Example 68-(7) to obtain Compound 4
(252 mg) as a colorless solid.
[1218] MS (m/z): 452 [M+H].sup.+
Example 96
[1219] (1)
##STR00809##
[1220] Starting from Compound 1 (230 mg) and Compound 2 (302 mg), a
treatment was carried out in a manner similar to the Example 68-(6)
to obtain Compound 3 (274 mg) as a colorless viscous material.
[1221] MS (m/z): 610 [M+H].sup.+
(2)
##STR00810##
[1222] Starting from Compound 3 (273 mg), a treatment was carried
out in a manner similar to the Example 87-(2) to obtain Compound 4
(109 mg) as a colorless solid.
[1223] MS (m/z): 424 [M+H].sup.+
Example 97
[1224] (1)
##STR00811##
[1225] Starting from Compound 1 (230 mg) and Compound 2 (292 mg), a
treatment was carried out in a manner similar to the Example 68-(6)
to obtain Compound 3 (195 mg) as a pale yellowish brown viscous
material.
[1226] MS (m/z): 554 [M+H].sup.+
(2)
##STR00812##
[1227] Starting from Compound 3 (194 mg), a treatment was carried
out in a manner similar to the Example 68-(7) to obtain Compound 4
(109 mg) as a colorless solid.
[1228] MS (m/z): 410 [M+H].sup.+
Example 98
[1229] (1)
##STR00813##
[1230] Starting from Compound 1 (230 mg) and Compound 2 (314 mg), a
treatment was carried out in a manner similar to the Example 68-(6)
to obtain Compound 3 (145 mg) as a colorless viscous material.
[1231] MS (m/z): 626 [M+H].sup.+
(2)
##STR00814##
[1232] Starting from Compound 3 (144 mg), a treatment was carried
out in a manner similar to the Example 87-(2) to obtain Compound 4
(65.8 mg) as a colorless solid.
[1233] MS (m/z): 440 [M+H].sup.+
Example 99
[1234] (1)
##STR00815##
[1235] Starting from Compound 1 (1350 mg) and Compound 2 (1273 mg),
a treatment was carried out in a manner similar to the Example
68-(6) to obtain Compound 3 (1610 mg) as a pale yellowish brown
viscous material.
[1236] MS (m/z): 576 [M+H].sup.+
(2)
##STR00816##
[1237] Starting from Compound 3 (400 mg) and Compound 4 (209 mg), a
treatment was carried out in a manner similar to the Example 68-(5)
to obtain Compound 5 (331 mg) as a pale yellowish brown viscous
material.
[1238] MS (m/z): 646 [M+H].sup.+
(3)
##STR00817##
[1239] Starting from Compound 5 (329 mg), a treatment was carried
out in a manner similar to the Example 68-(7) to obtain Compound 6
(208 mg) as a colorless solid.
[1240] MS (m/z): 502 [M+H].sup.+
Example 100
[1241] (1)
##STR00818##
[1242] Starting from Compound 1 (400 mg) and Compound 2 (156 mg), a
treatment was carried out in a manner similar to the Example 69-(2)
to obtain Compound 3 (260 mg) as a colorless viscous material.
[1243] MS (m/z): 608 [M+H].sup.+
(2)
##STR00819##
[1244] Starting from Compound 3 (258 mg), a treatment was carried
out in a manner similar to the Example 68-(7) to obtain Compound 4
(175 mg) as a colorless solid.
[1245] MS (m/z): 464 [M+H].sup.+
Example 101
[1246] (1)
##STR00820##
[1247] Starting from Compound 1 (400 mg) and Compound 2 (99 .mu.L),
a treatment was carried out in a manner similar to the Example
68-(5) to obtain Compound 3 (340 mg) as a colorless solid.
[1248] MS (m/z): 596 [M+H].sup.+
(2)
##STR00821##
[1249] Starting from Compound 3 (338 mg), a treatment was carried
out in a manner similar to the Example 68-(7) to obtain Compound 4
(200 mg) as a colorless solid.
[1250] MS (m/z): 452 [M+H].sup.+
Example 102
[1251] (1)
##STR00822##
[1252] Starting from Compound 1 (260 mg) and Compound 2 (317 mg), a
treatment was carried out in a manner similar to the Example 68-(6)
to obtain Compound 3 (259 mg) as a pale yellow viscous
material.
[1253] MS (m/z): 626 [M+H].sup.+
(2)
##STR00823##
[1254] Starting from Compound 3 (258 mg), a treatment was carried
out in a manner similar to the Example 87-(2) to obtain Compound 4
(143 mg) as a pale yellow solid.
[1255] MS (m/z): 440 [M+H].sup.+
Example 103
[1256] (1)
##STR00824##
[1257] Starting from Compound 1 (2.03 g), a treatment was carried
out in a manner similar to the Example 88-(1) to obtain Compound 3
(791 mg) as a yellowish brown solid.
[1258] MS (m/z): 258/260 [M+H].sup.+
(2)
##STR00825##
[1259] Starting from Compound 3 (785 mg), a treatment was carried
out in a manner similar to the Example 88-(2) to obtain Compound 4
(593 mg) as a yellowish brown solid.
[1260] MS (m/z): 272/274 [M+H].sup.+
(3)
##STR00826##
[1261] Starting from Compound 4 (560 mg), a treatment was carried
out in a manner similar to the Example 61-(3) to obtain Compound 5a
(131 mg) and Compound 5b (369 mg) as a colorless solid and a pale
yellow solid respectively.
[1262] Compound 5a: MS (m/z): 402/404 [M+H].sup.+
[1263] Compound 5b: MS (m/z): 402/404 [M+H].sup.+
(4)
##STR00827##
[1264] Starting from Compound 5a (127 mg), a treatment was carried
out in a manner similar to the Example 79-(5) to obtain Compound 6a
(110 mg) as a colorless solid.
[1265] MS (m/z): 434/436 [M+H].sup.+
(5)
##STR00828##
[1266] Starting from Compound 6a (108 mg) and Compound 7 (74.6 mg),
a treatment was carried out in a manner similar to the Example
68-(5) to obtain Compound 8a (121 mg) as a colorless solid.
[1267] MS (m/z): 504/506 [M+H].sup.+
(6)
##STR00829##
[1268] Starting from Compound 8a (120 mg) and Compound 9 (87.3 mg),
a treatment was carried out in a manner similar to the Example
68-(6) to obtain Compound 10a (123 mg) as a colorless solid.
[1269] MS (m/z): 647 [M+H].sup.+
(7)
##STR00830##
[1270] Starting from Compound 10a (123 mg), a treatment was carried
out in a manner similar to the Example 68-(7) to obtain Compound 11
(84.2 mg) as a pale yellow solid.
[1271] MS (m/z): 503 [M+H].sup.+
Example 104
[1272] (1)
##STR00831##
[1273] Starting from Compound 1 (3.00 g) and Compound 2 (6.03 g), a
treatment was carried out in a manner similar to the Example 68-(6)
to obtain Compound 3 (2.07 g) as a pale yellow powder.
[1274] MS (m/z): 329 [M+H].sup.+
(2)
##STR00832##
[1275] Starting from Compound 3 (2060 mg), a treatment was carried
out in a manner similar to the Example 68-(1) to obtain Compound 4
(853 mg) as a pale yellow solid.
[1276] MS (m/z): 433 [M+H].sup.+
(3)
##STR00833##
[1277] Starting from Compound 4 (850 mg), a treatment was carried
out in a manner similar to the Example 68-(2) to obtain Compound 5
(480 mg) as a colorless solid.
[1278] MS (m/z): 399 [M+H].sup.+
(4)
##STR00834##
[1279] Starting from Compound 5 (64.0 mg), a treatment was carried
out in a manner similar to the Example 61-(5) to obtain Compound 6
(52.4 mg) as a colorless solid.
[1280] MS (m/z): 385 [M+H].sup.+
Example 105
[1281] (1)
##STR00835##
[1282] A reaction was carried out in a manner similar to the
Example 53-(1) using a mixture of Compounds 1a and 1b (200 mg) and
Compound 2 (216 mg) to obtain a mixture of Compounds 3a and 3b (243
mg) as a pale yellow solid.
[1283] MS (m/z): 526 [M+H].sup.+
(2)
##STR00836##
[1284] A reaction was carried out in a manner similar to the
Example 53-(2) using the mixture of Compounds 3a and 3b (240 mg) to
obtain a mixture of Compounds 4a and 4b (245 mg) as a pale yellow
oil.
[1285] MS (m/z): 436 [M+H].sup.+
(3)
##STR00837##
[1286] A reaction was carried out in a manner similar to the
Example 55-(1) using the mixture of Compounds 4a and 4b (140 mg)
and Compound 5 (140 mg) to obtain a mixture of Compounds 6a and 6b
(111 mg) as a pale yellow oil. A reaction was carried out in a
manner similar to the Example 51-(5) using the mixture of Compounds
6a and 6b (110 mg) to obtain Compound 7 (17 mg) as a white
solid.
[1287] MS (m/z): 406 [M+H].sup.+
Example 106
[1288] (1)
##STR00838##
[1289] A reaction was carried out in a manner similar to the
Example 55-(1) using a mixture of Compounds 1a and 1b (150 mg) and
Compound 2 (120 mg) to obtain a mixture of Compounds 3a and 3b (140
mg) as a colorless solid.
[1290] MS (m/z): 593 [M+H].sup.+
(2)
##STR00839##
[1291] A reaction was carried out in a manner similar to the
Example 51-(5) using the mixture of Compounds 3a and 3b (140 mg) to
obtain Compound 4 (39 mg) as a colorless solid.
[1292] MS (m/z): 407 [M+H].sup.+
Example 107
[1293] (1)
##STR00840##
[1294] A mixture of Compound 1 (1.02 g), Compound 2 (1.10 g),
copper(I) bromide (40 mg), cesium carbonate (5.45 g) and
dimethylsulfoxide (20 mL) was stirred at 100.degree. C. for 16
hours. To the reaction solution were added 1N hydrochloric acid and
ethyl acetate, and the insoluble matter was removed by
celite-filtration. The filtrate was extracted with ethyl acetate,
and the extract was washed with water and saturated brine. The
extract was dried over anhydrous magnesium sulfate and
concentrated, and the residue was purified by silica gel column
chromatography (n-hexane:ethyl acetate=90:10 to 70:30) to obtain
Compound 3 (721 mg) as a colorless solid.
[1295] MS (m/z): 293/295 [M+H].sup.+
(2)
##STR00841##
[1296] A reaction was carried out in a manner similar to the
Example 50-(5) using Compound 3 (715 mg) to obtain Compound 4a (827
mg) and Compound 4b (144 mg) as colorless oils.
[1297] MS (m/z): 423/425 [M+H].sup.+
(3)
##STR00842##
[1298] A reaction was carried out in a manner similar to the
Example 50-(6) using Compound 4a (285 mg) and Compound 5 (362 mg)
to obtain Compound 6a (294 mg) as a pale yellow viscous
material.
[1299] MS (m/z): 552 [M+H].sup.+
(4)
##STR00843##
[1300] A reaction was carried out in a manner similar to the
Example 52-(7) using Compound 6a (287 mg) to obtain Compound 7 (251
mg) as a pale yellow viscous material.
[1301] MS (m/z): 538 [M+H].sup.+
(5)
##STR00844##
[1302] A reaction was carried out in a manner similar to the
Example 52-(8) using Compound 7 (243 mg) to obtain Compound 8 (114
mg) as a colorless powder.
[1303] MS (m/z): 408 [M+H].sup.+
Example 108
[1304] (1)
##STR00845##
[1305] A solution of Compound 1 (5 g), EDC hydrochloride (7.46 g)
and HOBt (5.26 g) in N,N-dimethylformamide (50 mL) was stirred at
room temperature for 2 hours. This solution was added dropwise to a
solution of hydrazine hydrate (3.16 mL) in acetonitrile (50 mL) at
0.degree. C., and the mixture was stirred at the same temperature
for 1 hour and further at room temperature for 30 minutes. The
deposit was removed by filtration, and a saturated aqueous sodium
hydrogen carbonate solution and ethyl acetate were added to the
filtrate, and the mixture was extracted. The extract was washed
with saturated brine and dried over anhydrous sodium sulfate, and
the solvent was distilled off. To the residue were added 4N
hydrogen chloride/dioxane (3 mL) and diethyl ether, and the mixture
was stirred. The deposit was filtered and vacuum-dried to obtain
Compound 2 (1335 mg) as a colorless powder.
[1306] MS (m/z): 169 [M+H].sup.+
(2)
##STR00846##
[1307] A reaction was carried out in a manner similar to the
Example 50-(6) using Compound 3 (4 g) and Compound 4 (7.37 g) to
obtain Compound 5 (6.26 g) as a colorless solid.
[1308] MS (m/z): 311 [M+H].sup.+
(3)
##STR00847##
[1309] A mixture of Compound 5 (6.24 g), a 50% aqueous hydroxyamine
solution (26.6 g), methanol (45 mL) and tetrahydrofuran (45 mL) was
stirred at 80.degree. C. for 2 hours. After the solvent was
distilled off, chloroform and water were added and the mixture was
extracted. The extract was washed with saturated brine, and dried
over anhydrous magnesium sulfate. The solvent was distilled off and
vacuum-dried to obtain Compound 6 (6.93 g) as a colorless
solid.
[1310] MS (m/z): 344 [M+H].sup.+
(4)
##STR00848##
[1311] To a solution of Compound 6 (6.92 g) in acetic acid (20 mL)
was added acetic anhydride (3.34 mL), and the mixture was stirred
at room temperature for 2 hours. The solvent was distilled off, the
residue was dissolved in methanol (100 mL), 10% palladium-carbon
was added under a nitrogen stream, and the mixture was stirred
under a hydrogen atmosphere at room temperature for 6 hours. The
catalyst was filtered off by a membrane-filter, the solvent was
distilled off, and subsequently diethyl ether was added. The
deposit was collected by filtration and vacuum-dried to obtain
Compound 7 (6.71 g) as a pale yellow solid.
[1312] MS (m/z): 328 [M+H].sup.+
(5)
##STR00849##
[1313] A mixture of Compound 7 (400 mg), Compound 2 (211 mg),
sodium methylate (167 mg) and ethanol (6 mL) was stirred at
100.degree. C. for 17 hours. The temperature of the reaction
solution was brought to room temperature, and ethyl acetate, 1N
hydrochloric acid and water were added, and the reaction solution
was extracted. After the extract was washed with saturated brine
and passed through the phase separator, the solvent was distilled
off. The residue was purified by silica gel column chromatography
(n-hexane:ethyl acetate=70:30 to 45:55) to obtain Compound 8 (276
mg) as a colorless oil.
[1314] MS (m/z): 461 [M+H].sup.+
(6)
##STR00850##
[1315] A reaction was carried out in a manner similar to the
Example 50-(8) using Compound 8 (275 mg) to obtain Compound 9 (262
mg) as a colorless solid.
[1316] MS (m/z): 447 [M+H].sup.+
Example 109
[1317] (1)
##STR00851##
[1318] A mixture of Compound 1 (400 mg), Compound 2 (127 mg),
sodium methylate (112 mg), ammonium chloride (55 mg) and
N,N-dimethylformamide (6 mL) was stirred at 100.degree. C. for 25
hours. The reaction solution was cooled to room temperature, and
ethyl acetate, a saturated aqueous ammonium chloride solution and
water were added, and the mixture was extracted. After the extract
was washed with saturated brine and passed through the phase
separator, the solvent was distilled off. The residue was purified
by silica gel column chromatography (n-hexane:ethyl acetate=70:30
to 45:55) to obtain Compound 3 (112 mg) as a pale yellow viscous
material.
[1319] MS (m/z): 395 [M+H].sup.+
(2)
##STR00852##
[1320] A reaction was carried out in a manner similar to the
Example 50-(8) using Compound 3 (112 mg) to obtain Compound 4 (72
mg) as a pale yellow solid.
[1321] MS (m/z): 381 [M+H].sup.+
Example 110
[1322] (1)
##STR00853##
[1323] A reaction was carried out in a manner similar to the
Example 109-(1) using Compound 1 (200 mg) and Compound 2 (103 mg)
to obtain Compound 3 (65 mg) as a pale yellow viscous material.
[1324] MS (m/z): 459 [M+H].sup.+
(2)
##STR00854##
[1325] A reaction was carried out in a manner similar to the
Example 50-(8) using Compound 3 (180 mg) to obtain Compound 4 (145
mg) as a colorless solid.
[1326] MS (m/z): 445 [M+H].sup.+
Example 111
[1327] (1)
##STR00855##
[1328] A reaction was carried out in a manner similar to the
Example 109-(1) using Compound 1 (400 mg) and Compound 2 (180 mg)
to obtain Compound 3 (234 mg) as a pale yellow viscous
material.
[1329] MS (m/z): 409 [M+H].sup.+
(2)
##STR00856##
[1330] A reaction was carried out in a manner similar to the
Example 50-(8) using Compound 3 (218 mg) to obtain Compound 4 (149
mg) as a colorless solid.
[1331] MS (m/z): 395 [M+H].sup.+
Example 112
[1332] (1)
##STR00857##
[1333] A reaction was carried out in a manner similar to the
Example 50-(6) using Compound 1 (297 mg) and Compound 2 (300 mg) to
obtain Compound 3 (292 mg) as a colorless viscous material.
[1334] MS (m/z): 566 [M+H].sup.+
(2)
##STR00858##
[1335] A reaction was carried out in a manner similar to the
Example 52-(7) using Compound 3 (288 mg) to obtain Compound 4 (305
mg) as a colorless viscous material.
[1336] MS (m/z): 552 [M+H].sup.+
(3)
##STR00859##
[1337] A reaction was carried out in a manner similar to the
Example 52-(8) using Compound 4 (280 mg) to obtain Compound 5 (149
mg) as a colorless solid.
[1338] MS (m/z): 422 [M+H].sup.+
Example 113
[1339] (1)
##STR00860##
[1340] A reaction was carried out in a manner similar to the
Example 85-(1) using Compound 1 (5.3 g) to obtain Compound 2 (4.05
g) as a beige solid.
[1341] MS (m/z): 275/277 [M+H].sup.+
(2)
##STR00861##
[1342] A reaction was carried out in a manner similar to the
Example 85-(2) using Compound 2 (4.03 g) to obtain Compound 3 (3.13
g) as a yellow solid.
[1343] MS (m/z): 289/291 [M+H].sup.+
(3)
##STR00862##
[1344] A reaction was carried out in a manner similar to the
Example 50-(5) using Compound 3 (3.1 g) to obtain Compound 4a (2.55
g) as a colorless viscous material and Compound 4b (1.70 g) as a
colorless solid.
[1345] 4a: MS (m/z): 419/421 [M+H].sup.+
[1346] 4b: MS (m/z): 419/421 [M+H].sup.+
(4)
##STR00863##
[1347] A reaction was carried out in a manner similar to the
Example 68-(4) using Compound 4b (1.62 g) to obtain Compound 5
(1.355 g) as a colorless solid.
[1348] MS (m/z): 451/453 [M+H].sup.+
(5)
##STR00864##
[1349] A reaction was carried out in a manner similar to the
Example 50-(6) using Compound 5 (300 mg) and Compound 6 (255 mg) to
obtain Compound 7 (347 mg) as a colorless solid.
[1350] MS (m/z): 594 [M+H].sup.+
(6)
##STR00865##
[1351] To a solution of isopropanol (77 mg) in tetrahydrofuran (3
mL) was added 60% sodium hydride (35 mg) at 0.degree. C., and the
mixture was stirred for 10 minutes. To this was added a solution of
Compound 7 (345 mg) in tetrahydrofuran (3 mL), and the mixture was
stirred for 10 minutes. A 2N aqueous sodium hydroxide solution (2.9
mL) and methanol (3 mL) were then added, and the mixture was
stirred at room temperature overnight. The reaction solution was
concentrated, the residue was neutralized with 1N hydrochloric
acid, and the mixture was extracted with ethyl acetate. The extract
was washed with saturated brine, and dried over anhydrous magnesium
sulfate. After the extract was concentrated under reduced pressure,
the obtained residue was purified by silica gel column
chromatography (n-hexane:ethyl acetate=100:0 to 90:10) to obtain
Compound 8 (279 mg) as a colorless viscous material.
[1352] MS (m/z): 560 [M+H].sup.+
(7)
##STR00866##
[1353] A reaction was carried out in a manner similar to the
Example 88-(7) using Compound 8 (278 mg) to obtain Compound 9 (60
mg) as a colorless solid.
[1354] MS (m/z): 430 [M+H].sup.+
Example 114
[1355] (1)
##STR00867##
[1356] Starting from Compound 1 (389 mg) and 3-pentanol (120 mg), a
reaction was carried out in a manner similar to the Example 113-(6)
to obtain Compound 2 (292 mg) as a colorless viscous material.
[1357] MS (m/z): 570 [M+H].sup.+
(2)
##STR00868##
[1358] Starting from Compound 2 (290 mg), a reaction was carried
out in a manner similar to the Example 88-(7) to obtain Compound 3
(60 mg) as a colorless solid.
[1359] MS (m/z): 439 [M+H].sup.+
Example 115
[1360] (1)
##STR00869##
[1361] A mixture of Compound 1 (230 mg), potassium ferrocyanide
(II) tetrahydrate (66 mg), palladium acetate (9 mg), butyl
di-1-adamantylphosphine (42 mg), sodium carbonate (17 mg) and
N-methylpyrrolidone (5 mL) was stirred under a nitrogen atmosphere
at 160.degree. C. for 18 hours. To the reaction solution was added
water, and the mixture was extracted with ethyl acetate. The
extract was washed with saturated brine and dried over anhydrous
magnesium sulfate. After the extract was concentrated under reduced
pressure, the obtained residue was purified by silica gel column
chromatography (n-hexane:ethyl acetate=100:0 to 80:20) to obtain
Compound 2 (24 mg) as a colorless viscous material.
[1362] MS (m/z): 580 [M+H].sup.+
(2)
##STR00870##
[1363] A reaction was carried out in a manner similar to the
Example 88-(7) using Compound 2 (20 mg) to obtain Compound 3 (11
mg) as a colorless solid.
[1364] MS (m/z): 436 [M+H].sup.+
Example 116
[1365] (1)
##STR00871##
[1366] Starting from Compound 1 (300 mg) and cyclobutanol (75 mg),
the reaction was carried out in a manner similar to the Example
113-(6) to obtain Compound 2 (270 mg) as a colorless powder.
[1367] MS (m/z): 554 [M+H].sup.+
(2)
##STR00872##
[1368] A reaction was carried out in a manner similar to the
Example 88-(7) using Compound 2 (270 mg) to obtain Compound 3 (110
mg) as a colorless solid.
[1369] MS (m/z): 424 [M+H].sup.+
Example 117
[1370] (1)
##STR00873##
[1371] A reaction was carried out in a manner similar to the
Example 51-(2) using Compound 1 (2.15 g) and Compound 2 (2.8 g) to
obtain Compound 3 (2.82 g) as a pale pink solid.
[1372] MS (m/z): 314/316 [M+H].sup.+
(2)
##STR00874##
[1373] A mixture of Compound 3 (2.81 g), Compound 4 (2.73 g),
bis(triphenylphosphine)palladium(II) chloride (190 mg), potassium
acetate (2.63 g) and dioxane (56 mL) was stirred under a nitrogen
atmosphere at 100.degree. C. for 4 hours. The reaction solution was
filtered through Celite, and the mixture was washed with ethyl
acetate. The filtrate was washed with saturated brine, and dried
over anhydrous magnesium sulfate. After the filtrate was
concentrated under reduced pressure, the obtained residue was
purified by silica gel column chromatography (n-hexane:ethyl
acetate=100:0 to 90:10) to obtain Compound 5 (1.384 g) as a
colorless solid.
[1374] MS (m/z): 362 [M+H].sup.+
(3)
##STR00875##
[1375] A reaction was carried out in a manner similar to the
Example 50-(6) using Compound 5 (392 mg) and Compound 6 (400 mg) to
obtain Compound 7 (383 mg) as a colorless viscous material.
[1376] MS (m/z): 588 [M+H].sup.+
(4)
##STR00876##
[1377] A reaction was carried out in a manner similar to the
Example 113-(6) using Compound 7 (380 mg) and cyclobutanol (93 mg)
to obtain Compound 8 (293 mg) as a colorless solid.
[1378] MS (m/z): 566 [M+H].sup.+
(5)
##STR00877##
[1379] Starting from Compound 8 (290 mg), the reaction was carried
out in a manner similar to the Example 88-(7) to obtain Compound 9
(190 mg) as a colorless solid.
[1380] MS (m/z): 436 [M+H].sup.+
Example 118
[1381] (1)
##STR00878##
[1382] A reaction was carried out in a manner similar to the
Example 113-(6) using Compound 1 (300 mg) and cyclobutanol (56 mg)
to obtain Compound 2 (305 mg) as a colorless viscous material.
[1383] MS (m/z): 554 [M+H].sup.+
(2)
##STR00879##
[1384] A reaction was carried out in a manner similar to the
Example 88-(7) using Compound 2 (304 mg) to obtain Compound 3 (142
mg) as a colorless solid.
[1385] MS (m/z): 424 [M+H].sup.+
Example 119
[1386] (1)
##STR00880##
[1387] A reaction was carried out in a manner similar to the
Example 50-(6) using Compound 1 (367 mg) and Compound 2 (400 mg) to
obtain Compound 3 (515 mg) as a colorless viscous material.
[1388] MS (m/z): 588 [M+H].sup.+
(2)
##STR00881##
[1389] A reaction was carried out in a manner similar to the
Example 113-(6) using Compound 3 (513 mg) and cyclobutanol (126 mg)
to obtain Compound 4 (463 mg) as a colorless solid.
[1390] MS (m/z): 566 [M+H].sup.+
(3)
##STR00882##
[1391] A reaction was carried out in a manner similar to the
Example 88-(7) using Compound 4 (460 mg) to obtain Compound 5 (286
mg) as a colorless solid.
[1392] MS (m/z): 436 [M+H].sup.+
Example 120
[1393] (1)
##STR00883##
[1394] Starting from Compound 1 (290 mg) and 2-methyl-1-propanol
(56 mg), the reaction was carried out in a manner similar to the
Example 113-(6) to obtain Compound 2 (199 mg) as a colorless
viscous material.
[1395] MS (m/z): 556 [M+H].sup.+
(2)
##STR00884##
[1396] Starting from Compound 2 (198 mg), the reaction was carried
out in a manner similar to the Example 88-(7) to obtain Compound 3
(74 mg) as a colorless solid.
[1397] MS (m/z): 426 [M+H].sup.+
Example 121
[1398] (1)
##STR00885##
[1399] A reaction was carried out in a manner similar to the
Example 113-(6) using Compound 1 (290 mg) and cyclopropylmethanol
(54 mg) to obtain Compound 2 (287 mg) as a colorless viscous
material.
[1400] MS (m/z): 554 [M+H].sup.+
(2)
##STR00886##
[1401] Starting from Compound 2 (286 mg), the reaction was carried
out in a manner similar to the Example 88-(7) to obtain Compound 3
(61 mg) as a colorless solid.
[1402] MS (m/z): 424 [M+H].sup.+
Example 122
[1403] (1)
##STR00887##
[1404] A treatment was carried out in a manner similar to the
Example 113-(6) using Compound 1 (290 mg) and cyclobutylmethanol
(65 mg) to obtain Compound 2 (279 mg) as a colorless viscous
material.
[1405] MS (m/z): 568 [M+H].sup.+
(2)
##STR00888##
[1406] A reaction was carried out in a manner similar to the
Example 88-(7) using Compound 2 (278 mg) to obtain Compound 3 (107
mg) as a colorless solid.
[1407] MS (m/z): 438 [M+H].sup.+
Example 123
[1408] (1)
##STR00889##
[1409] Starting from Compound 1 (350 mg) and 2-methyl-1-propanol
(90 mg), the reaction was carried out in a manner similar to the
Example 113-(6) to obtain Compound 2 (319 mg) as a colorless
viscous material.
[1410] MS (m/z): 556 [M+H].sup.+
(2)
##STR00890##
[1411] A reaction was carried out in a manner similar to the
Example 88-(7) using Compound 2 (317 mg) to obtain Compound 3 (111
mg) as a colorless solid.
[1412] MS (m/z): 426 [M+H].sup.+
Example 124
[1413] (1)
##STR00891##
[1414] A reaction was carried out in a manner similar to the
Example 113-(6) using Compound 1 (350 mg) and cyclopropylmethanol
(88 mg) to obtain Compound 2 (345 mg) as a colorless viscous
material.
[1415] MS (m/z): 554 [M+H].sup.+
(2)
##STR00892##
[1416] Starting from Compound 2 (343 mg), a reaction was carried
out in a manner similar to the Example 88-(7) to obtain Compound 3
(129 mg) as a colorless solid.
[1417] MS (m/z): 424 [M+H].sup.+
Example 125
[1418] (1)
##STR00893##
[1419] A reaction was carried out in a manner similar to the
Example 113-(6) using Compound 1 (350 mg) and cyclobutylmethanol
(209 mg) to obtain Compound 2 (345 mg) as a colorless viscous
material.
[1420] MS (m/z): 568 [M+H].sup.+
(2)
##STR00894##
[1421] Starting from Compound 2 (343 mg), a reaction was carried
out in a manner similar to the Example 88-(7) to obtain Compound 3
(115 mg) as a colorless solid.
[1422] MS (m/z): 438 [M+H].sup.+
Example 126
[1423] (1)
##STR00895##
[1424] Starting from Compound 1 (300 mg) and cyclopentanol (119
mg), a reaction was carried out in a manner similar to the Example
68-(5) to obtain Compound 2 (300 mg) as a colorless solid.
[1425] MS (m/z): 439/441 [M+H].sup.+
(2)
##STR00896##
[1426] A reaction was carried out in a manner similar to the
Example 68-(6) using Compound 2 (298 mg) and Compound 3 (261 mg) to
obtain Compound 4 (359 mg) as a colorless viscous material.
[1427] MS (m/z): 582 [M+H].sup.+
(3)
##STR00897##
[1428] A reaction was carried out in a manner similar to the
Example 88-(7) using Compound 2 (355 mg) to obtain Compound 4 (178
mg) as a colorless solid.
[1429] MS (m/z): 438 [M+H].sup.+
Example 127
[1430] (1)
##STR00898##
[1431] A treatment was carried out in a manner similar to the
Example 68-(5) using Compound 1 (400 mg) and cyclopentanol (177 mg)
to obtain Compound 2 (332 mg) as a colorless viscous material.
[1432] MS (m/z): 395/397 [M+H].sup.+
(2)
##STR00899##
[1433] Starting from Compound 2 (330 mg) and Compound 3 (350 mg), a
treatment was carried out in a manner similar to the Example 68-(6)
to obtain Compound 4 (304 mg) as a colorless viscous material.
[1434] MS (m/z): 582 [M+H].sup.+
(3)
##STR00900##
[1435] A treatment was carried out in a manner similar to the
Example 88-(7) using Compound 4 (303 mg) to obtain Compound 5 (139
mg) as a colorless solid.
[1436] MS (m/z): 438 [M+H].sup.+
Reference Example 1
##STR00901##
[1438] Compound 1 (2'-(trifluoromethoxy)acetophenone) (1.00 g),
N-bromosuccinimide (0.87 g) and toluene sulfonic acid monohydrate
(84 mg) were stirred at room temperature overnight. Dichloromethane
and saturated brine were added to the reaction solution to carry
out a liquid separation. The organic layer was separated and dried
over anhydrous sodium sulfate, and subsequently the solvent was
distilled off under reduced pressure. The obtained residue was
purified by silica gel column chromatography (n-hexane:ethyl
acetate=99:1 to 94:6) to obtain Compound 2 (1.14 g).
[1439] NMR (400 MHz, DMSO-d.sub.6): 7.97 (1H, dd, J=8.0, 4.0 Hz),
7.75 (1H, m), 7.57 (1H, t, J=8.0 Hz), 7.53 (1H, d, J=8.0 Hz), 4.85
(1H, s)
Reference Example 2
##STR00902##
[1440] (1) Compound 1 (2'-hydroxyacetophenone) (1.20 mL),
2-bromoethyl methyl ether (1.88 mL) and cesium carbonate (3.26 g)
were dissolved in N,N-dimethylformamide (10 mL), and the mixture
was stirred at 90.degree. C. overnight. After the temperature of
the reaction solution was brought back to room temperature, ethyl
acetate and water were added to carry out a liquid separation. The
organic layer was separated, washed with saturated brine, and dried
over anhydrous magnesium sulfate. The solvent was distilled off
under reduced pressure. The obtained residue was purified by silica
gel column chromatography (n-hexane:ethyl acetate=95:5 to 80:20) to
obtain Compound 2 (1.75 g).
[1441] MS (m/z): 195 [M+H].sup.+
(2) A treatment was carried out in a manner similar to Reference
Example 1 using Compound 2 (1.74 g) to obtain Compound 3 (2.24
g).
[1442] MS (m/z): 273/275 [M+H].sup.+
Reference Example 3
##STR00903##
[1443] (1) Compound 1 (2'-hydroxyacetophenone) (0.60 mL) was
dissolved in dimethylsulfoxide (25 mL), 2-iodopropane (1.70 g) and
potassium phosphate (2.12 g) were added, and the mixture was
stirred at 60.degree. C. for 4 hours. After the temperature of the
reaction solution was brought back to room temperature, ethyl
acetate and water were added to carry out a liquid separation. The
organic layer was separated, washed with saturated brine, and dried
over anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure. The obtained residue was purified by silica gel
column chromatography (n-hexane:ethyl acetate=98:2 to 92:8) to
obtain Compound 2 (0.74 g).
[1444] MS (m/z): 179 [M+H].sup.+
(2) Compound 2 (200 mg) was dissolved in ethyl acetate (2.5 mL) and
chloroform (2.5 mL), copper bromide (0.50 g) was added, and the
mixture was heated at reflux under a nitrogen atmosphere for 4
hours. After the temperature of the reaction solution was brought
back to room temperature, the reaction solution was filtered
through Celite and washed with ethyl acetate. The filtrate was
concentrated under reduced pressure and the obtained residue was
purified by silica gel column chromatography (n-hexane:ethyl
acetate=98:2 to 92:8) to obtain Compound 3 (267 mg).
[1445] MS (m/z): 257/259 [M+H].sup.+
Reference Example 4
##STR00904##
[1447] Compound 1 (2'-fluoro-6'-(trifluoromethyl)acetophenone) (500
mg) was dissolved in tetrahydrofuran (10 mL),
benzyltrimethylammonium tribromide (1.04 g) was added, and the
mixture was stirred at room temperature for 2 hours. The reaction
solution was concentrated under reduced pressure, to the residue
was added diethyl ether, and the obtained solid was filtered and
washed by diethyl ether. The filtrate was concentrated under
reduced pressure, and the obtained residue was purified by silica
gel column chromatography (n-hexane:ethyl acetate=99:1 to 95:5) to
obtain Compound 2 (632 mg).
[1448] NMR (400 MHz, DMSO-d.sub.6): 7.77 (3H, m), 4.83 (1H, d,
J=1.2 Hz)
Reference Example 5
##STR00905##
[1450] Compound 1 (4-methoxy-2-(trifluoromethyl)benzoic acid) (0.50
g) was dissolved in dichloromethane (10 mL), and oxalyl chloride
(0.40 mL) was added dropwise. To this was added
N,N-dimethylformamide (5 drops), and the mixture was stirred at
room temperature for 1 hour. After the reaction solution was
concentrated under reduced pressure, acetonitrile (10 mL) was
added. A 2M trimethylsilyldiazomethane-n-hexane solution (2.4 mL)
was added dropwise under ice cooling, and the mixture was stirred
at room temperature for 1 hour. The reaction solution was
ice-cooled, a 48% hydrobromic acid (0.39 mL) was added dropwise,
and the mixture was stirred for 1 hour. Ethyl acetate and a
saturated aqueous sodium hydrogen carbonate solution were added to
the reaction solution to carry out a liquid separation. The organic
layer was separated and dried over anhydrous sodium sulfate, and
subsequently the solvent was distilled off under reduced pressure.
The obtained residue was purified by silica gel column
chromatography (n-hexane:ethyl acetate=98:2 to 92:8) to obtain
Compound 2 (0.44 g).
[1451] MS (m/z): 297/299 [M+H].sup.+
Reference Example 6
##STR00906##
[1452] (1) Compound 1 (3-acetylbenzoic acid) (500 mg) was dissolved
in N,N-dimethylformamide (10 mL), potassium carbonate (421 mg) and
benzyl bromide (362 .mu.L) were added, and the mixture was stirred
at room temperature overnight. Ethyl acetate and water were added
to the reaction solution to carry out a liquid separation, the
organic layer was dried over anhydrous sodium sulfate, and the
solvent was distilled off under reduced pressure. The obtained
residue was purified by silica gel column chromatography
(n-hexane:ethyl acetate=99:1 to 85:15) to obtain Compound 2 (763
mg).
[1453] MS (m/z): 272 [M+NH.sub.4].sup.+
(2) A treatment was carried out in a manner similar to Reference
Example 1 using Compound 2 (760 mg) to obtain Compound 3 (668
mg).
[1454] MS (m/z): 333/335 [M+H].sup.+
Reference Example 7-1
##STR00907##
[1455] (1) Compound 1 (4-bromophenol) (61.0 g), Compound 2 (methyl
hydroxypivalate) (69.9 g) and triphenylphosphine (138.7 g) were
dissolved in tetrahydrofuran (350 mL), and the mixture was cooled
to 0.degree. C. under a nitrogen atmosphere. Subsequently, a 40%
diethyl azodicarboxylate-toluene solution (240 mL) was added
dropwise, and the mixture was stirred while the temperature was
brought back to room temperature and then at 80.degree. C.
overnight. After the temperature of the reaction solution was
brought back to room temperature, the reaction solution was
concentrated under reduced pressure, to the obtained residue was
added diethyl ether (500 mL), and the obtained solid was filtered
and washed with diethyl ether. The filtrate was concentrated under
reduced pressure and the obtained residue was purified by silica
gel column chromatography (n-hexane:ethyl acetate=100:0, 19:1 and
to 9:1) to obtain Compound 3 (102.2 g).
[1456] MS (m/z): 304/306 [M+NH.sub.4].sup.+
(2) Compound 3 (102.2 g), bis(pinacolato)diboron (98.5 g),
[1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (7.73
g), 1,1'-bis(diphenylphosphino)ferrocene (5.86 g), and potassium
acetate (103.8 g) were added to 1,4-dioxane (470 mL), and the
mixture was stirred under a nitrogen atmosphere at 80.degree. C.
overnight. After the temperature of the reaction solution was
brought back to room temperature, the reaction solution was
concentrated under reduced pressure, and ethyl acetate and water
were added to the obtained residue to carry out a liquid
separation. The organic layer was separated, washed with saturated
brine, and dried over anhydrous sodium sulfate. The solvent was
distilled off under reduced pressure. The obtained residue was
purified by silica gel column chromatography (n-hexane:ethyl
acetate=100:0, 9:1 and to 4:1), to the obtained residue was added
n-hexane, and the mixture was stirred under ice-cooling for 1 hour.
The obtained solid was collected by filtration and dried to obtain
Compound 4 (95.5 g).
[1457] MS (m/z): 335 [M+H].sup.+
(3) Compound 4 (87.6 g) and Compound 5 (2-chloro-5-cyanopyridine)
(40.0 g) were dissolved in dimethoxyethane (550 mL), and a 2M
aqueous sodium carbonate solution (525 mL) was added. To this was
added tetrakis(triphenylphosphine)palladium (21.2 g) under a
nitrogen atmosphere, and the mixture was stirred at 90.degree. C.
overnight. After the temperature of the reaction solution was
brought back to room temperature, ethyl acetate and water were
added to carry out a liquid separation. The organic layer was
separated, washed with saturated brine, and dried over anhydrous
magnesium sulfate. The solvent was distilled off under reduced
pressure. The obtained residue was purified by silica gel column
chromatography (n-hexane:ethyl acetate=9:1, 4:1 and to 2:1) to
obtain Compound 6 (77.4 g).
[1458] MS (m/z): 311 [M+H].sup.+
(4) Compound 6 (6.27 g) was dissolved in tetrahydrofuran (100 mL)
and methanol (100 mL), a 50% aqueous hydroxylamine solution (40 mL)
was added, and the mixture was stirred at 80.degree. C. for 4
hours. After the temperature of the reaction solution was brought
back to room temperature, the reaction solution was concentrated
under reduced pressure, and chloroform and water were added to the
obtained residue to carry out a liquid separation. The organic
layer was separated, washed with saturated brine, and dried over
anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure to obtain Compound 7 (6.70 g).
[1459] MS (m/z): 344 [M+H].sup.+
(5) Compound 7 (6.68 g) was dissolved in acetic acid (60 mL),
acetic anhydride (4 mL) was added, and the mixture was stirred at
room temperature for 1.75 hours. After the reaction solution was
concentrated under reduced pressure, to the obtained residue were
added tetrahydrofuran (70 mL) and methanol (300 mL), 10%
palladium/carbon (1.25 g) was added under a nitrogen atmosphere,
and the mixture was subjected to hydrogen substitution, and stirred
at room temperature for 2 hours. The reaction solution was
filtered, and the residue was washed with methanol. After the
filtrate was concentrated under reduced pressure, ethyl acetate was
added to the residue, and the obtained deposit was washed with
ethyl acetate and dried to obtain Compound 8 (6.81 g) as an acetate
salt.
[1460] MS (m/z): 328 [M+H].sup.+
Reference Examples 7-2 to 7-19
[1461] A treatment was carried out in a manner similar to Reference
Example 7-1 to obtain compounds of Reference Examples 7-2 to 7-19
in Table 27 below.
TABLE-US-00027 TABLE 27 Reference Example Intermediate 1
Intermediate 2 7-2 ##STR00908## ##STR00909## 7-3 ##STR00910##
##STR00911## 7-4 ##STR00912## ##STR00913## 7-5 ##STR00914##
##STR00915## 7-6 ##STR00916## ##STR00917## 7-7 ##STR00918##
##STR00919## 7-8 ##STR00920## ##STR00921## 7-9 ##STR00922##
##STR00923## 7-10 ##STR00924## ##STR00925## 7-11 ##STR00926##
##STR00927## 7-12 ##STR00928## ##STR00929## 7-13 ##STR00930##
##STR00931## 7-14 ##STR00932## ##STR00933## 7-15 ##STR00934##
##STR00935## 7-16 ##STR00936## ##STR00937## 7-17 ##STR00938##
##STR00939## 7-18 ##STR00940## ##STR00941## 7-19 ##STR00942##
##STR00943## Reference Example Product MS (m/z) 7-2 ##STR00944##
328 [M + H].sup.+ 7-3 ##STR00945## 342 [M + H].sup.+ 7-4
##STR00946## 342 [M + H].sup.+ 7-5 ##STR00947## 356 [M + H].sup.+
7-6 ##STR00948## 343 [M + H].sup.+ 7-7 ##STR00949## 344 [M +
H].sup.+ 7-8 ##STR00950## 403 [M + H].sup.+ 7-9 ##STR00951## 330 [M
+ H].sup.+ 7-10 ##STR00952## 360 [M + H].sup.+ 7-11 ##STR00953##
398 [M + H].sup.+ 7-12 ##STR00954## 341 [M + H].sup.+ 7-13
##STR00955## 415 [M + H].sup.+ 7-14 ##STR00956## 414 [M + H].sup.+
7-15 ##STR00957## 397 [M + H].sup.+ 7-16 ##STR00958## 384 [M +
H].sup.+ 7-17 ##STR00959## 400 [M + H].sup.+ 7-18 ##STR00960## 356
[M + H].sup.+ 7-19 ##STR00961## 342 [M + H].sup.+
Reference Example 8
##STR00962##
[1463] Compound 1 (4.9 g) and Compound 2 (5 g) were dissolved in
N,N-dimethylformamide (50 mL), and a 60% sodium hydride (1.16 g)
was added portionwise under ice cooling. The temperature of the
reaction solution was elevated to room temperature, and the
reaction solution was stirred for 4 hours. After a saturated
aqueous ammonium chloride solution was added under ice cooling,
ethyl acetate and water were added to carry out a liquid
separation. The organic layer was separated, washed with water, and
dried over sodium sulfate. The solvent was distilled off under
reduced pressure. The obtained residue was purified by silica gel
column chromatography (n-hexane:ethyl acetate=100:0 to 97:3) to
obtain Compound 3 (6.71 g).
[1464] MS (m/z): 356/358 [M+H].sup.+
Reference Example 9-1
##STR00963##
[1466] Compound 1 (1.46 g), Compound 2 (1.46 g), a
dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium
(PdCl.sub.2(dppf))-methylene chloride complex (399 mg) and a 2N
aqueous cesium carbonate solution (7.33 mL) were added to
1,4-dioxane (29 mL), and the mixture was stirred at 100.degree. C.
for 5 hours. The reaction solution was filtered, and ethyl acetate
and water were added to the filtrate to carry out a liquid
separation. The organic layer was separated, washed with saturated
brine and dried over anhydrous sodium sulfate. The solvent was
distilled off under reduced pressure. The obtained residue was
purified by silica gel column chromatography (n-hexane:ethyl
acetate=95:5 to 80:20) and solidified by n-hexane to obtain
Compound 3 (1.39 g).
[1467] MS (m/z): 367 [M+H].sup.+
Reference Examples 9-2 to 9-3
[1468] A treatment was carried out in a manner similar to Reference
Example 9-1 to obtain compounds of Reference Examples 9-2 and 9-3
in Table 28 below.
TABLE-US-00028 TABLE 28 Reference Example Intermediate 1
Intermediate 2 Product MS (m/z) 9-2 ##STR00964## ##STR00965##
##STR00966## 313 [M + H].sup.+ 9-3 ##STR00967## ##STR00968##
##STR00969## 383 [M + H].sup.+
Reference Example 10
##STR00970##
[1469] (1) A treatment was carried out in a manner similar to
Reference Example 7-1 (4) using Compound 1 (850 mg) to obtain
Compound 2 (940 mg).
[1470] MS (m/z): 392/394 [M+H].sup.+
(2) Compound 2 (925 mg) was dissolved in acetic acid (9 mL) and
acetic anhydride (268 .mu.L), and the mixture was stirred at room
temperature for 30 minutes. Palladium chloride (46 mg) and triethyl
silane (535 .mu.L) were added, and the mixture was stirred at
70.degree. C. for 4 hours. Additional triethyl silane (288 .mu.L)
was added, and the mixture was further stirred at the same
temperature for 30 minutes. The reaction solution was filtered, and
the filtrate was concentrated under reduced pressure. Saturated
brine and ethyl acetate were added to the obtained residue to carry
out a liquid separation. The organic layer was separated, washed
with saturated brine, and dried over anhydrous magnesium sulfate.
The solvent was distilled off under reduced pressure. The obtained
residue was purified by NH-silica gel column chromatography
(chloroform:methanol=100:0 to 90:10) and then silica gel column
chromatography (n-hexane:ethyl acetate=90:10 to 67:33) to obtain
Compound 3 (201 mg).
[1471] MS (m/z): 376/378 [M+H].sup.+
Reference Example 11
##STR00971##
[1472] (1) A treatment was carried out in a manner similar to
Reference Example 7-1 (4) using Compound 1 (1.4 g) to obtain
Compound 2 (1.51 g).
[1473] MS (m/z): 451 [M+H].sup.+
(2) Compound 2 (1.32 g) was dissolved in acetic acid (30 mL) and
acetic anhydride (610 .mu.L), and the mixture was stirred at room
temperature for 6 hours. To the reaction solution were added
methanol (10 mL) and tetrahydrofuran (10 mL), and 10%
palladium-carbon (265 mg) was added under a nitrogen atmosphere.
The reaction mixture was stirred under a hydrogen atmosphere at
room temperature for 2 hours and subsequently filtered through
Celite, and the filtrate was concentrated under reduced pressure.
To the obtained residue were added ethanol (20 mL) and a 4N
hydrogen chloride-dioxane solution (10 mL), and the mixture was
stirred at room temperature overnight and further at 60.degree. C.
for 8 hours. Chloroform, methanol and an aqueous saturated sodium
hydrogen carbonate solution were added to the reaction solution to
carry out a liquid separation. The organic layer was separated,
dried over anhydrous sodium sulfate and concentrated under reduced
pressure. The obtained residue was solidified with diethyl ether to
obtain Compound 3 (675 mg).
[1474] MS (m/z): 373 [M+H].sup.+
Reference Example 12
##STR00972##
[1475] (1) Compound 1 (1.86 g), Compound 2 (3.02 g) and a 28%
aqueous ammonia (25 mL) were added to a mixed solvent of water (25
mL) and methanol (100 mL), and the mixture was stirred at room
temperature for 5 hours. Chloroform and a saturated aqueous sodium
hydrogen carbonate solution were added to the residue obtained by
concentration of the reaction solution under reduced pressure to
carry out a liquid separation. The organic layer was separated and
dried with anhydrous sodium sulfate, and subsequently the solvent
was distilled off under reduced pressure. The obtained residue was
purified by silica gel column chromatography (n-hexane:ethyl
acetate=50:50 to 20:80) to obtain Compound 3 (490 mg).
[1476] MS (m/z): 300/302 [M+H].sup.+
(2) To a solution of Compound 3 (475 mg) in N,N-dimethylformamide
(5 mL) was added a 60% sodium hydride (95 mg) under a nitrogen
atmosphere under ice cooling, and the mixture was stirred at room
temperature for 30 minutes. To this was added
2-(trimethylsilyl)ethoxymethyl chloride (420 .mu.L) under ice
cooling, and the mixture was stirred at room temperature for 6
hours. To the reaction solution was added a saturated aqueous
ammonium chloride solution, and the mixture was extracted with
ethyl acetate. The organic layer was washed with saturated brine,
and the aqueous layer thus obtained was extracted with ethyl
acetate. The organic layers were combined, dried and concentrated
under reduced pressure. The obtained residue was purified by silica
gel column chromatography (n-hexane:ethyl acetate=87:13 to 74:26)
to obtain Compound 4 (651 mg).
[1477] MS (m/z): 430/431 [M+H].sup.+
Reference Example 13-1
##STR00973##
[1478] (1) To water (15 mL) were added Compound 1
(3,3-dibromo-1,1,1-trifluoropropan-2-one) (4.05 g) and sodium
acetate (2.46 g), and the mixture was stirred at 95.degree. C. for
30 minutes. The reaction solution was ice-cooled, this was added to
a solution of Compound 2 (6-bromo-nicotinaldehyde) (1.86 g)
dissolved in a 28% aqueous ammonia solution (20 mL) and methanol
(60 mL) under ice-cooling, and the mixture was stirred overnight
while the temperature was gradually elevated to room temperature.
After the reaction solution was concentrated under reduced
pressure, water and ethyl acetate were added to carry out a liquid
separation, the organic layer was dried over anhydrous sodium
sulfate, and the solvent was distilled off under reduced pressure.
Diethyl ether was added to the obtained solid residue, the mixture
was triturated and solid was collected by filtration and dried to
obtain Compound 3
(2-bromo-5-[5-(trifluoromethyl)-1H-imidazole-2-yl]pyridine) (1.25
g).
[1479] MS (m/z): 292/294 [M+H].sup.+
(2) To a solution of Compound 3
(2-bromo-5-[5-(trifluoromethyl)-1H-imidazole-2-yl]pyridine) (13.65
g) dissolved in N,N-dimethylformamide (150 mL) was added a 60%
sodium hydride (2.62 g) under a nitrogen atmosphere under
ice-cooling, and the mixture was stirred for 30 minutes. To this
was added 2-(trimethylsilyl)ethoxymethyl chloride (12.4 mL) under
ice cooling, and the mixture was stirred overnight while the
temperature gradually brought back to room temperature. To the
reaction solution was added a saturated aqueous ammonium chloride
solution, and the mixture was extracted with ethyl acetate. The
organic layer was washed with saturated brine, and the aqueous
layer thus obtained was extracted with ethyl acetate. The organic
layers were combined, dried and concentrated under reduced
pressure. The obtained residue was purified by silica gel column
chromatography (n-hexane:ethyl acetate) to obtain Compound 4
(2-bromo-5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-i-
midazole-2-yl]pyridine) (9.42 g).
[1480] MS (m/z): 422/424 [M+H].sup.+
Reference Examples 13-2 to 13-3
[1481] A treatment was carried out in a manner similar to Reference
Example 13-1 to obtain compounds of Reference Examples 13-2 to 13-3
in Table 29 below.
TABLE-US-00029 TABLE 29 Reference MS Example Starting material 1
Starting material 2 Product (m/z) 13-2 ##STR00974## ##STR00975##
##STR00976## 422/424 [M + H].sup.+ 13-3 ##STR00977## ##STR00978##
##STR00979## 421/423 [M + H].sup.+
Reference Example 14
##STR00980##
[1483] A treatment was carried out in a manner similar to the
Example 11 (1) using Compound 1 (1.0 g) to obtain Compound 2 (2.68
g).
[1484] MS (m/z): 382/384 [M+H].sup.+
Reference Example 15-1
##STR00981##
[1485] (1) Compound 1 (5.9 g) was dissolved in ethanol (70 mL), and
an 8M aqueous sodium hydroxide solution (25 mL) was added, and the
mixture was stirred at 70.degree. C. for 19 hours. The reaction
solution was concentrated under reduced pressure, and ethyl acetate
and water were added to the obtained residue to carry out a liquid
separation. The aqueous layer was separated, and to this was added
a 6M hydrochloric acid to adjust the pH to 5-6. Further, after
neutralization by addition of phosphate buffer (pH 7.0), the
mixture was extracted with a mixed solvent of ethyl acetate and
tetrahydrofuran. The organic layer was separated, dried over
anhydrous sodium sulfate, and concentrated under reduced pressure.
To the obtained residue was added diethyl ether, and the deposited
solid was collected by filtration to obtain Compound 2 (2.56
g).
[1486] MS (m/z): 268/270 [M+H].sup.+
(2) Compound 2 (2.62 g), diisopropyl ethyl amine (2.21 mL) and
benzyl bromide (2.01 g) were added to N,N-dimethylacetamide (30
mL), and the mixture was stirred at room temperature overnight. The
reaction mixture was ice-cooled, water (270 mL) was added, and the
obtained solid was collected by filtration and washed with n-hexane
to obtain Compound 3 (3.06 g).
[1487] MS (m/z): 358/360 [M+H].sup.+
(3) A treatment was carried out in a manner similar to the Example
6 (2) using Compound 3 (2.88 g) to obtain Compound 4 (1.76 g).
[1488] MS (m/z): 488/490 [M+H].sup.+
Reference Example 15-2
[1489] A treatment was carried out in a manner similar to Reference
Example 15-1 to obtain a compound of Reference Example 15-2 in
Table 30 below.
TABLE-US-00030 TABLE 30 Reference MS Example Intermediate Product
(m/z) 15-2 ##STR00982## ##STR00983## 487/489 [M + H].sup.+
Reference Example 16
##STR00984##
[1490] (1) To a solution of sodium methylate (1.39 g) in methanol
(28.9 mL) was added Compound 1 (6-chloronicotinonitrile) (10 g),
and the mixture was stirred at 40.degree. C. for 30 minutes. The
reaction solution was concentrated under reduced pressure, to the
obtained residue was added tetrahydrofuran (30 mL) to be mixed, and
the mixture was concentrated under reduced pressure. To the residue
was added tetrahydrofuran (100 mL), glycine methyl ester
hydrochloride (9.06 g) and triethylamine (11.07 mL) were added, and
the mixture was stirred at 55.degree. C. for 6.5 hours. The
deposited solid was collected by filtration, washed with ethyl
acetate and dried to obtain Compound 2 (19.05 g).
[1491] MS (m/z): 196/198 [M+H].sup.+
(2) Compound 2 (19.05 g) was heated in phosphorous oxychloride
(45.4 mL) at reflux for 1.5 hours. The insoluble matter was
filtered, and the filtrate was neutralized by addition of aethyl
acetate and a 2N aqueous sodium hydroxide solution. Tetrahydrofuran
and activated charcoal were added, the mixture was stirred and
filtered thought Celite, and water and ethyl acetate were added to
the filtrate to carry out a liquid separation. The organic layer
was separated, washed with brine, and dried over anhydrous
magnesium sulfate. The solvent was distilled off under reduced
pressure. To the obtained solid was added acetonitrile, and the
solid was collected by filtration and dried to obtain Compound 3
(4.87 g).
[1492] MS (m/z): 214/216 [M+H].sup.+
(3) A treatment was carried out in a manner similar to the Example
6 (2) using Compound 3 (5.09 g) to obtain Compound 4 (5.96 g).
[1493] MS (m/z): 344/346 [M+H].sup.+
Reference Example 17-1
##STR00985##
[1494] (1) Palladium acetate (924 mg) and
2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl
(X-PHOS) (5.88 g) were added to a mixed solvent of 1,4-dioxane (500
mL) and water (297 .mu.L) under a nitrogen atmosphere, and the
mixture was stirred at 80.degree. C. for 10 minutes. After the
reaction solution was cooled to room temperature, a separately
prepared solution of Compound 1 (50.00 g), Compound 2 (45.97 g) and
cesium carbonate (100.52 g) in 1,4-dioxane (500 mL) was added, and
the mixture was stirred at 100.degree. C. for 4 hours. The reaction
solution was cooled and subsequently filtered through Celite, and
Celite was washed with ethyl acetate. The obtained filtrate was
washed with water and then saturated brine, and dried over
anhydrous sodium sulfate. Subsequently, the solvent was distilled
off under reduced pressure. The obtained residue was purified by
silica gel column chromatography (n-hexane:ethyl acetate=100:0 to
80:20) to obtain Compound 3 (69.14 g).
[1495] MS (m/z): 349 [M+H].sup.+
(2) Compound 3 (186.80 g) was dissolved in tetrahydrofuran (525
mL), and the solution was ice-cooled. A 4N hydrochloric
acid-1,4-dioxane solution (656 mL) was slowly added, and the
mixture was stirred at room temperature overnight. The reaction
solution was concentrated under reduced pressure, the obtained
residue was crystallized after addition of t-butyl methyl ether,
and the crystals were collected by filtration. The obtained
crystals were suspended in ethyl acetate, a 2M aqueous sodium
hydroxide solution was added to adjust the pH to 9, and the mixture
was extracted with ethyl acetate. The organic layer was dried over
anhydrous sodium sulfate, and subsequently the solvent was
distilled off under reduced pressure. The obtained residue was
purified by silica gel column chromatography (n-hexane:ethyl
acetate=80:20 to 0:100) to obtain Compound 4 (129.64 g).
[1496] MS (m/z): 249 [M+H].sup.+
(3) Compound 4 (3.32 g), Compound 5 (2.36 g) and potassium
carbonate (2.35 g) were added to dimethylsulfoxide (50 mL), and the
mixture was stirred at 100.degree. C. for 2 hours. After the
mixture was cooled to room temperature, ethyl acetate and water
were added to carry out a liquid separation. The organic layer was
separated, washed with saturated brine, and dried over anhydrous
sodium sulfate. The solvent was distilled off under reduced
pressure. The obtained residue was purified by silica gel column
chromatography (n-hexane:ethyl acetate=80:20 to 0:100). The
purified product was triturated in diethyl ether and collected by
filtration to obtain Compound 6 (3.24 g).
[1497] MS (m/z): 351 [M+H].sup.+
Reference Example 17-2
[1498] A treatment was carried out in a manner similar to Reference
Example 17-1 to obtain a compound of Reference Example 17-2 in
Table 31 below.
TABLE-US-00031 TABLE 31 Reference MS Example Starting material 1
Starting material 2 Product (m/z) 17-2 ##STR00986## ##STR00987##
##STR00988## 318 [M + H].sup.+
Reference Example 18
##STR00989##
[1499] (1) A treatment was carried out in a manner similar to
Reference Example 7-1) using Compound 1 (7.08 g) and Compound 2
(2.5 g) to obtain Compound 3 (2.78 g).
[1500] MS (m/z): 350 [M+H].sup.+
(2) Compound 3 (2.78 g) was dissolved in 1,4-dioxane (10 mL), and a
4N hydrogen chloride-1,4-dioxane solution (20 mL) was added under
ice cooling. The reaction solution was stirred at room temperature
overnight, and diethyl ether was added. The deposited solid was
collected by filtration, washed with diethyl ether and then dried
to obtain Compound 4 (2.27 g).
[1501] MS (m/z): 250 [M+H].sup.+
(3) Compound 4 (600 mg), Compound 5 (500 mg), potassium carbonate
(871 mg) and 1,8-diazabicyclo[5.4.0]undec-7-ene (345 .mu.L) were
added to 1,4-dioxane (15 mL), and the mixture was stirred at
99.degree. C. for two days. After the reaction solution was
concentrated under reduced pressure, ethyl acetate and water were
added to carry out a liquid separation. The organic layer was
separated, washed with water and saturated brine, and dried over
anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure. The obtained residue was purified by silica gel
column chromatography (n-hexane:ethyl acetate=100:0 to 70:30). To
the obtained solid were added ethyl acetate and n-hexane under ice
cooling, and the deposit was collected by filtration to obtain
Compound 6 (515 mg).
[1502] MS (m/z): 352 [M+H].sup.+
Reference Example 19
##STR00990##
[1503] (1) A treatment was carried out in a manner similar to
Reference Example 7-1 (1) using Compound 1 (7.64 g) and Compound 2
(5.0 g) to obtain Compound 3 (8.27 g).
[1504] MS (m/z): 210 [M+H].sup.+
(2) Compound 3 (3.0 g) was dissolved in diethyl ether (20 mL),
benzyl bromide (3.4 mL) was added, and the mixture was stirred at
room temperature for two days. Subsequently, the deposited solid
was collected by filtration. The solid was dissolved in methanol
(60 mL), sodium borohydride (2.17 g) was added portionwise, and the
mixture was stirred at room temperature for 2 hours. After a
saturated aqueous ammonium chloride solution and methylene chloride
were added to carry out a liquid separation, the organic layer was
separated, washed with saturated brine, and concentrated under
reduced pressure. The obtained residue was dissolved in methanol
(60 mL), a 10% palladium-carbon (300 mg) was added, and the mixture
was stirred under a hydrogen atmosphere for 7 hours. The 10%
palladium-carbon was filtered out and the filtrate was concentrated
under reduced pressure. The residue was dissolved in acetic acid
(50 mL), a 10% palladium-carbon (300 mg) was added, and the mixture
was stirred under a hydrogen atmosphere at 70.degree. C. for 7
hours. The 10% palladium-carbon was filtered out, the filtrate was
concentrated under reduced pressure, and the obtained residue was
purified by NH-silica gel column chromatography
(chloroform:methanol=100:0 to 98:2) to obtain Compound 4 (1.34
g).
[1505] MS (m/z): 216 [M+H].sup.+
Reference Example 20-1
##STR00991##
[1507] A treatment was carried out in a manner similar to Reference
Example 7-1 (4) and Reference Example 7-1 (5) using Compound 1 (514
mg) to obtain Compound 2 (416 mg) as an acetate salt.
[1508] MS (m/z): 369 [M+H].sup.+
Reference Examples 20-2 to 20-3
[1509] A treatment was carried out in a manner similar to Reference
Example 20-1 to obtain compounds of Reference Examples 20-2 and
20-3 in Table 32 below.
TABLE-US-00032 TABLE 32 Reference MS Example Intermediate Product
(m/z) 20-2 ##STR00992## ##STR00993## 368 [M + H].sup.+ 20-3
##STR00994## ##STR00995## 335 [M + H].sup.+
Reference Example 21-1
##STR00996##
[1510] (1) Compound 1 (4-bromophenol) (61.0 g), Compound 2 (methyl
hydroxypivalate) (69.9 g) and triphenylphosphine (138.7 g) were
dissolved in tetrahydrofuran (350 mL), and the mixture was cooled
to 0.degree. C. under a nitrogen atmosphere. Subsequently, a 40%
diethyl azodicarboxylate-toluene solution (240 mL) was added
dropwise, and the mixture was stirred while the temperature brought
back to room temperature and then at 80.degree. C. overnight. After
the temperature of the reaction solution was brought back to room
temperature, the reaction solution was concentrated under reduced
pressure, and to the obtained residue was added diethyl ether (500
mL). The obtained solid was filtered and washed with diethyl ether.
The filtrate was concentrated under reduced pressure and the
obtained residue was purified by silica gel column chromatography
(n-hexane:ethyl acetate=100:0, 19:1 and to 9:1) to obtain Compound
3 (102.2 g).
[1511] MS (m/z): 304/306 [M+NH.sub.4].sup.+
(2) Compound 3 (102.2 g), bis(pinacolato)diboron (98.5 g), a
[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride
dichloromethane complex (7.73 g),
1,1'-bis(diphenylphosphino)ferrocene (5.86 g) and potassium acetate
(103.8 g) were dissolved in 1,4-dioxane (470 mL), and the mixture
was stirred under a nitrogen atmosphere at 80.degree. C. overnight.
After the temperature of the mixture was brought back to room
temperature, the mixture was concentrated under reduced pressure,
and ethyl acetate and water were added to the obtained residue to
carry out a liquid separation. The organic layer was separated,
washed with saturated brine, and dried over anhydrous sodium
sulfate. The solvent was distilled off under reduced pressure. The
obtained residue was purified by silica gel column chromatography
(n-hexane:ethyl acetate=100:0, 9:1 and to 4:1), and to the obtained
residue was added n-hexane, and the mixture was stirred under
ice-cooling for 1 hour. The solid was collected by filtration and
dried to obtain Compound 4 (95.5 g).
[1512] MS (m/z): 335 [M+H].sup.+
Reference Examples 21-2 to 21-9
[1513] A reaction was carried out in a manner similar to Reference
Example 21-1 using the following raw materials 1 and 2 to obtain
compounds of Reference Examples 21-2 to 21-9 in Table 33 below.
TABLE-US-00033 TABLE 33 Reference MS Example Raw Material 1 Raw
Material 2 Product 4 (m/z) 21-2 ##STR00997## ##STR00998##
##STR00999## 336 [M + H].sup.+ 21-3 ##STR01000## ##STR01001##
##STR01002## 350 [M + H].sup.+ 21-4 ##STR01003## ##STR01004##
##STR01005## 350 [M + H].sup.+ 21-5 ##STR01006## ##STR01007##
##STR01008## 348 [M + H].sup.+ 21-6 ##STR01009## ##STR01010##
##STR01011## 362 [M + H].sup.+ 21-7 ##STR01012## ##STR01013##
##STR01014## 404 [M + H].sup.+ 21-8 ##STR01015## ##STR01016##
##STR01017## 420 [M + H].sup.+ 21-9 ##STR01018## ##STR01019##
##STR01020## 424 [M + H].sup.+
Reference Example 22-1
##STR01021##
[1514] (1) To a solution of dimethyl 1,1-cyclohexanedicarboxylate
(2.08 g) in methanol (15 mL) was added a 1N aqueous sodium
hydroxide solution (13.2 mL), and the mixture was stirred at room
temperature for 23 hours. The methanol was distilled off under
reduced pressure, and the residue was washed with n-hexane. To an
aqueous layer was added 1N hydrochloric acid (10 mL), and the
mixture was extracted with chloroform. The extract was washed with
saturated brine, and dried over anhydrous magnesium sulfate. After
drying, concentration under reduced pressure provided Compound 2
(1.58 g) as a colorless oil. (2) A solution of Compound 2 (1.57 g)
in tetrahydrofuran (15 mL) was ice-cooled under a nitrogen stream,
and a 1M solution of a borane/tetrahydrofuran complex in
tetrahydrofuran (12 mL) was added dropwise. After dropwise
addition, the reaction solution was stirred at room temperature for
1.5 hours. The reaction solution was ice-cooled, and methanol was
added. After the mixture was concentrated under reduced pressure,
the residue was dissolved in methanol (15 mL), 20% hydrochloric
acid/methanol (4 mL) was added, and the mixture was stirred at
70.degree. C. for 18 hours. The reaction solution was concentrated
under reduced pressure, to the residue was added an aqueous
saturated sodium bicarbonate solution, and the mixture was
extracted with chloroform. The extract was washed with saturated
brine, and dried over anhydrous magnesium sulfate. To this was
added NH silica gel, and the mixture was stood. The mixture was
filtered and concentrated under reduced pressure to obtain Compound
3 (1.14 g) as a colorless oil.
[1515] MS (m/z): 131 [M+H].sup.+
Reference Example 22-2
##STR01022##
[1516] (1) To a solution of dibenzyl malonate (25 g) in
N,N-dimethylformamide (250 mL) were added potassium carbonate
(121.5 g) and dibromoethane (22.7 mL), and the mixture was stirred
at room temperature overnight. To the reaction solution was added
water, and the mixture was extracted with ethyl acetate. The
extract was washed with water, dried over anhydrous sodium sulfate,
and then concentrated under reduced pressure. The obtained residue
was purified by silica gel column chromatography (n-hexane:ethyl
acetate=90:10 to 80:20) to obtain Compound 2 (25.33 g) as a
colorless oil. (2) A solution of Compound 2 (16.9 g) in methylene
chloride (338 mL) was cooled to -65.degree. C. or lower, and a 1M
diisobutylaluminum hydride/toluene solution (119.8 mL) was added
dropwise. After dropwise addition, the temperature of the reaction
solution was elevated to -15.degree. C. over 30 minutes. To the
reaction solution were added a saturated aqueous ammonia chloride
solution (170 mL) and 1N hydrochloric acid (170 mL), and the
mixture was stirred for 10 minutes. To the obtained gel-like
mixture was added further 1N hydrochloric acid (300 mL) to dissolve
the mixture. The organic layer was separated, washed with saturated
sodium bicarbonate water, and dried over anhydrous sodium sulfate.
After concentration under reduced pressure, the residue was
purified by silica gel column chromatography (n-hexane:ethyl
acetate=90:10 to 50:50) to obtain Compound 3 (5.18 g) as a
colorless oil.
[1517] MS (m/z): 207 [M+H].sup.+
Reference Example 22-3
##STR01023##
[1518] (1) To a solution of dimethyl diethylmalonate (25 g) in
methanol (250 mL) was added a 1N aqueous sodium hydroxide solution
(132.8 mL), and the mixture was stirred at room temperature
overnight. The methanol was distilled off under reduced pressure,
and the residue was washed with methylene chloride. To the aqueous
layer was added 1N hydrochloric acid to adjust the pH to 3, and the
mixture was extracted with diethyl ether. The extract was washed
with water, dried over anhydrous magnesium sulfate. After drying,
concentration under reduced pressure provided Compound 2 (23.1 g)
as a colorless oil. (2) Anhydrous magnesium sulfate (63.85 g) was
suspended in methylene chloride (230 mL), concentrated sulfuric
acid (7.07 mL) was added dropwise at room temperature, and the
mixture was stirred for 15 minutes. To this was added a solution of
Compound 2 (23.1 g) in methylene chloride (115 mL), and then
tert-butanol (63.5 mL) was added. The reaction solution was stirred
at room temperature overnight. The reaction mixture was filtered,
and the filtrate was ice-cooled and rendered alkaline with an
aqueous saturated sodium hydrogen carbonate solution. The organic
layer was separated, washed with saturated brine, dried over
anhydrous sodium sulfate and concentrated under reduced pressure to
obtain Compound 3 (26.09 g) as a colorless oil. (3) To a solution
of the obtained Compound 3 (14 g) in tetrahydrofuran (140 mL) was
added dropwise a 1M solution of lithium tri(tert-butoxy)aluminum
hydride in tetrahydrofuran (150 mL) at room temperature, and the
mixture was gradually heated and then at reflux for 8 hours. The
reaction solution was ice-cooled, and 1N hydrochloric acid (500 mL)
was added dropwise. The reaction mixture was extracted with diethyl
ether, and the extract was washed with water and an aqueous
saturated sodium bicarbonate solution, and dried over anhydrous
magnesium sulfate. After concentration under reduced pressure, the
residue was purified by silica gel column chromatography
(n-hexane:ethyl acetate=90:10 to 80:20) to obtain Compound 4 (7.41
g) as a colorless oil.
[1519] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) (ppm): .delta. 4.48 (t,
J=5.2 Hz, 1H), 3.42 (d, J=5.1 Hz, 2H), 1.46 (m, 4H), 1.38 (s, 9H),
0.74 (t, J=7.2 Hz, 6H)
Reference Example 22-4
##STR01024##
[1520] (1) To a solution of diethyl 1,1-cyclobutanedicarboxylate
(25 g) in ethanol (250 mL) was added a 1N aqueous sodium hydroxide
solution (125 mL), and the mixture was stirred at room temperature
for 6 days. The ethanol was distilled off under reduced pressure,
and the residue was washed with diethyl ether. To the aqueous layer
was added 1N hydrochloric acid to adjust the pH to 3, and the
mixture was extracted with chloroform. The extract was washed with
water, dried over anhydrous magnesium sulfate. After drying,
concentration under reduced pressure provided Compound 2 (20.67 g)
as a colorless oil. (2) Anhydrous magnesium sulfate (52 g) was
suspended in methylene chloride (186 mL), concentrated sulfuric
acid (5.8 mL) was added dropwise at room temperature, and the
mixture was stirred for 15 minutes. To this was added a solution of
Compound 2 (18.6 g) in methylene chloride (93 mL), and then
tert-butanol (52 mL) was added. The reaction solution was stirred
at room temperature overnight. The reaction mixture was filtered,
and the filtrate was ice-cooled and rendered alkaline with an
aqueous saturated sodium bicarbonate solution. The organic layer
was separated, washed with saturated brine, dried over anhydrous
sodium sulfate, and concentrated under reduced pressure to obtain
Compound 3 (24.7 g) as a colorless oil. (3) To a solution of the
obtained Compound 3 (15.9 g) in tetrahydrofuran (160 mL) was added
dropwise a 1M solution of lithium tri(tert-butoxy)aluminum hydride
(153 mL) in tetrahydrofuran at room temperature, and the mixture
was gradually heated and then at reflux for 3.5 hours. The reaction
solution was ice-cooled, a saturated aqueous ammonium chloride
solution was added, and the mixture was stirred at room
temperature. The obtained gel-like mixture was filtered, and
concentrated under reduced pressure. Subsequently, the residue was
purified by silica gel column chromatography (n-hexane:ethyl
acetate=100:0 to 75:25) to obtain Compound 4 (11.02 g) as a
colorless oil.
[1521] MS (m/z): 187 [M+H].sup.+
(4) To a solution of Compound 4 (3 g) in methanol (60 mL) was added
2N hydrochloric acid/methanol (6 mL), and the mixture was heated at
reflux for 5.5 hours. The reaction solution was diluted with
methylene chloride, washed with an aqueous saturated sodium
bicarbonate solution and saturated brine, dried over anhydrous
magnesium sulfate and concentrated under reduced pressure to obtain
Compound 5 (2.16 g) as a colorless oil.
[1522] MS (m/z): 149 [M+H].sup.+
Experimental Example 1
DGAT1 Inhibitory Activity
Experimental Method
(1) Cloning of Human DGAT1 Gene and Preparation of Recombinant
Baculovirus
[1523] Human DGAT1 gene was obtained by using a human cDNA library
as a temple, and amplifying the base sequence (245-1711 in Genbank
Accession No. NM.sub.--012079) which codes DGAT1 by PCR
reaction.
[1524] Thus obtained human DGAT1 gene was ligated into a plasmid,
pVL1392 (BD Biosciences) to prepare an expression plasmid,
pVL1392-DGAT1. Further, a recombinant baculovirus was prepared by
using BD BaculoGold Baculovirus Expression vector system (BD
Biosciences).
(2) Preparation of Microsome of Human DGAT 1 Enzyme Highly
Expressed-Insect Cell
[1525] The preparation of human DGAT 1 enzyme was carried out by
infecting the recombinant baculovirus obtained in the previous item
with expresSF+.RTM. insect cell (Nosan Corporation). After the
recombinant baculovirus was added to the expresSF+.RTM. cell and
the mixture was cultivated for 72 hours, the cells were collected
by centrifugation, and freeze-preserved at -80.degree. C. The
freeze-preserved cells were fused in an ice water, suspended in a
buffer (200 mM Sucrose, 1 mM EDTA, 100 mM Tris-HCl (pH7.4)) to
which Complete Protease Inhibitor (Roche) had been added, and
subjected to a sonication. Then, a microsome fraction was obtained
by an ordinary method and freeze-preserved at -80.degree. C. as a
highly DGAT1-expressing microsome.
(3) Measurement of DGAT1 Inhibitory Activity
[1526] As a buffer used for the enzymatic reaction of DGAT1, 100 mM
Tris-HCl (pH7.4), 200 mM Sucrose, and 20 mM MgCl.sub.2, 0.125%
Bovin Serum Albumin (BSA) were used. To this buffer, a test
compound with predetermined concentration of test compound, 15
.mu.M dioleylglycerol, 5 .mu.M [.sup.14C]-palmitoyl-CoA, 100
.mu.g-protein/mL, highly DGAT1-expressing expresSF+.RTM. microsome,
0.75% acetone, and 1% dimethylsulfoxide were added, and a
triglyceride (TG) synthesis reaction in a volume of 100 .mu.L was
carried out at 30.degree. C. for 20 minutes. 90 .mu.L of the
reaction solution was added to 810 .mu.L of methanol to cease the
reaction. The reaction solution was added to Oasis.RTM. .mu.
Elution plate (Waters) and eluted with 150 .mu.L of mixture of
acetonitrile:isopropanol (=2:3). 150 .mu.L of MicroScinti.TM.-40
(Perkin-Elmer Corp.) were added to the eluted solution and the
mixture was sufficiently stirred, and an amount of [.sup.14C]-TG
produced in the reaction was determined by measuring using
TopCount.TM.-NXT (Perkin-Elmer Corp.).
[1527] The inhibitory ratio was calculated by the following
equation.
Inhibitory ratio(%)=(1-(TG amount when the test compound was
added-blank TG amount)/(control TG amount-blank TG
amount)).times.100
[1528] Here, a count of [.sup.14C]-TG in the solution where the
reaction was carried out without adding the test compound was
regarded "control TG amount", and a count of [.sup.14C]-TG in the
solution to which the test compound and highly DGAT1 expressing
expresSF+.RTM. microsome were not added was regarded as "blank TG
amount". Further, a concentration of test compound required to
inhibit the synthesis of [.sup.14C]-TG by 50% (IC.sub.50 value) was
calculated by Prism 5.01 (GraphPad Softwear).
Experimental Result
[1529] The experimental results are shown in Table 34 as below.
TABLE-US-00034 TABLE 34 Example IC.sub.50 (nM) Example IC.sub.50
(nM) 1-1 8.0 1-3 6.9 1-17 11 1-28 16.9 1-31 26.6 1-34 2.1 1-35 13
1-37 11 1-44 4.2 1-58 11 1-63 3.3 1-68 19 2-7 2.5 2-8 2.9 2-11 3.7
2-16 5.7 3-7 2.5 4-1 1.7 4-3 2.1 4-15 0.94 5-2 3.2 6 9.1 7 11 8 6.1
9 7.9 10 6.4 11 44.4 12 4.7 14 3.2 17 2.9 21-2 6.9 23-1 3.3 24-2 26
25 36 29-3 15 30 29 31-2 6.8 32-2 1.7 34 8.8 35-1 2.7 37-3 4.3 37-4
14 37-6 21 38-5 20 39 16 40-1, Compound 4 12 42 24 43-1 8.5 43-2 16
43-3 16 43-7 17 44-6 0.78 44-11 25 45-1 1.5 46-1 9.0 46-4 4.4 46-5
1.2 47-1 9.0 48 8.2 49 17 51 15 52 21 55 8.1 57 76 59 2.6 60 18 61
5.2 67 3.9 108 5.0 109 12 110 1.1 72 2.2 75 1.1 74 1.1 77 28 78 1.7
80 3.3 82 4.6 83 1.8 104 6.8
Experimental Example 2
(Triglyceride (TG) Elevation-Suppressing Action in Plasma by Lipid
Administration)
Experimental Method
[1530] Male ICR mice, 6 to 9 weeks old, were fasted overnight, and
a test compound was suspended in 0.2% carboxymethylcellulose
solution and the suspension was orally administered. After 30
minutes, lipid (Intralipos, 20%, Otsuka Pharmaceutical, 10 mL/kg)
was orally administered. Blood was sampled through the caudal vein
immediately before and 2 hours after the administration of the
lipid to obtain plasma. TG in the plasma was determined by using
Triglyceride E-Test Wako (Wako Pure Chemical), and the elevation
value of TG in the plasma by the lipid administration was
calculated. By using the plasma TG elevation value in the solvent
control group as the control, the plasma TG elevation-suppressing
ratio was calculated in the test compound administrating group.
Experimental Result
[1531] As a result as the above, the test compound of the example
showed the plasma TG elevation-suppressing ratio at the dose of 5
mg/kg as shown in Table 35 as below.
TABLE-US-00035 TABLE 35 Plasma TG elevation Plasma TG elevation
suppressing ratio suppressing ratio Example (5 mg/kg) Example (5
mg/kg) 1-58 66% 2-11 62% 4-1 74% 7 47% 10 53% 31-2 74% 32-2 63%
37-3 64% 37-4 69% 43-1 66% 43-2 66% 46-5 59% 48 61% 51 49.3% 52
70.8% 59 72.0% 61 77.4% 67 56.8% 110 73.0% 75 74.6% 74 67.5% 78
73.8% 82 67.9% 83 79.5%
Experimental Example 3
Food Intake-Suppressing Action
Experimental Method
[1532] Male C57BL/6J mice, 7 to 10 weeks old, were fasted
overnight, and a test compound was suspended in 0.2%
carboxymethylcellulose solution and the suspension was orally
administered. Immediately, the animals were given high fat diet
(Oriental Yeast, 60 cal % fat) and allowed to take freely. The food
intake for 4 hours was determined, and the decrease ratio of the
food intake (food intake-suppressing ratio) was calculated in the
test compound administrating group, relative to the food intake in
the solvent control group as a control.
Experimental Result
[1533] The test compound of the example showed the food
intake-suppressing ratio at the dose of 5 mg/kg as shown in Table
36 as below.
TABLE-US-00036 TABLE 36 Food intake- suppressing Food intake- ratio
suppressing ratio Example (5 mg/kg) Example (5 mg/kg) 1-58 68% 2-11
55% 4-1 79% 7 73% 10 67% 31-2 74% 32-2 65% 37-3 69% 37-4 82% 43-1
40% 43-2 82% 46-5 54% 48 64% 51 65% 52 75% 59 73% 61 60% 67 50% 110
68% 75 70% 74 82% 78 44% 82 60% 83 59%
Experiment Example 4
Body Weight Gain-Suppressing Action, Hypoglycemic Action and Plasma
Insulin-Decreasing Action in KK-Ay Mouse
Experimental Method
[1534] Male KK-Ay mice, 8 weeks old, were given high fat diet
(Oriental Yeast, 60 cal % fat), the test compound was suspended in
0.2% carboxymethylcellulose solution and the suspension was orally
administered once a day. After the oral administration was repeated
for 2 weeks, the body weight gain-suppressing ratio of the test
compound was calculated, relative to the body weight gain of the
solvent control group during the test period as 100%. After the
final administration, the animals were fasted overnight, and blood
was sampled through the caudal vein. The blood sugar and the
insulin in the plasma were determined by using Glucose C II-Test
Wako (Wako Pure Chemical) and Mouse Insulin Measurement Kit
(Morinaga Institute of Biological Science), respectively.
Experimental Result
[1535] As a result as above, the test compound of the example
showed the hypoglycemic action, the plasma insulin-decreasing
action, and the body weight gain-suppressing action at the dose of
30 mg/kg/day as shown in Table 37 as below, relative to the solvent
control group.
TABLE-US-00037 TABLE 37 Hypoglycemic Plasma insulin- Body weight
gain- action decreasing action suppressing action Example (30
mg/kg/day) (30 mg/kg/day) (30 mg/kg/day) 7 42% 34% 34% 10 37% 40%
32% 31-2 55% 45% 41% 43-1 36% 53% 21% 51 26% 21% 41% 61 44% 50% 36%
67 47% 14% 43% 74 32% 29% 41% 78 57% 69% 56%
INDUSTRIAL APPLICABILITY
[1536] The continuation aromatic cyclic compound of the present
invention or a pharmaceutically acceptable salt thereof has an
excellent DGAT1 inhibitory action and can be used as a
prevention/treatment agent of obesity.
* * * * *